Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors

ABSTRACT

The present invention encompasses intermediates for preparing compounds of formula (I) 
                         
wherein the groups R 1  to R 4 , R 7 , A, D, E, F, V, W, X, Y, n, r and q are defined in claim  1 , their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions which contain compounds of this kind, their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases, and synthetic intermediates.

The present invention relates to newspiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives offormula (I)

wherein the groups R¹ to R⁴, R⁷, A, D, E, F, V, W, X, Y, n, r and q havethe meanings given in the claims and specification, their use asinhibitors of MDM2-p53 interaction, pharmaceutical compositions whichcontain compounds of this kind, their use as medicaments, especially asagents for treatment and/or prevention of oncological diseases, andsynthetic intermediates.

BACKGROUND OF THE INVENTION

The tumor suppressor protein p53 is a sequence specific transcriptionfactor and plays a central role in the regulation of several cellularprocesses, including cell cycle and growth arrest, apoptosis, DNArepair, senescence, angiogenesis, and innate immunity. The Mouse DoubleMinute 2 (MDM2) protein (or its human homolog also known as HDM2) actsto down-regulate p53 activity in an auto-regulatory manner, and undernormal cellular conditions (absence of stress), the MDM2 protein servesto maintain p53 activity at low levels. MDM2 directly inhibits thetransactivation function of p53, exports p53 out of the nucleus, andpromotes proteasome-mediated degradation of p53 through its E3 ubiquitinligase activity.

Deregulation of the MDM2/p53 balance by overexpression of MDM2 or by p53mutation or loss leads to malignant transformation of normal cells.Presently p53 is known to play a key role in practically all types ofhuman cancers, and the mutation or loss of the p53 gene can beidentified in more than 50% of all human cancers worldwide. Analysis of28 different types of human cancers in nearly 4,000 human tumor samplesshowed that MDM2 is amplified in 7% of human cancers and that MDM2overexpression by amplification and p53 mutations are largely mutuallyexclusive (Momand et al., Nucleic Acid Res (1998) 26:3453-3459).

Because of the powerful tumor suppressor function of p53, reactivationof p53 has been long sought as a potentially novel cancer therapeuticstrategy. In tumor harboring wild-type p53, MDM2 is the primary cellularinhibitor of p53 activity, and overexpression of MDM2 was found in manyhuman tumors. Since MDM2 inhibits p53 through a direct protein-proteininteraction, blocking this interaction using small molecules was pursuedin several academic and industrial pharmaceutical laboratories in thelast decade. A variety of non-peptide, drug-like small molecule as e.g.imidazole compounds (e.g. Nutlins or RG7112), benzodiazepinedionecompounds, spirooxindole compounds (e.g. MI-219), substitutedpiperidines, pyrrolidinone compounds (e.g. PXN820-dl) and modificationsthereof have been selected and designed in order to block MDM2/p53interaction as a means to reactivate p53 in cells (Vassilev et al.,Science (2004) 303:844-848; Grasberger et al., J Med Chem (2005)48:909-912; Parks et al., Bioorg Med Chem Lett (2005) 15:765; Ding etal., J Am Soc (2005) 127:10130-10131; WO 2010/028862, U.S. Pat. No.7,884,107, WO 2008/119741). A number of potent MDM2/p53 inhibitors havebeen evaluated in animal models of human cancer for their anti-tumoractivity (Vassilev et al., Science (2004) 303:844-848; Tovar et al,Cancer Res (2013) 73 (8): 2587-2597; Ding et al, Journal of MedicinalChemistry (2013) 56 (14): 5979-5983; Rew et al, Journal of MedicinalChemistry (2012) 55: 4936-4954; Sun et al, Journal of MedicinalChemistry (2014) 57 (4): 1454-1472).

In the pediatric preclinical testing program (PPTP) of the NCI, earlyevidence for high level anti-proliferative activity of RG7112, aninhibitor of the MDM2-p53 interaction, could be observed in vitro and invivo. In particular, RG-7112 showed cytotoxic activity with lower medianIC₅₀ values for p53 wild-type vs. p53 mutant cell lines (Carol et al.,Pediatric Blood and Cancer (2013) 60(4):633-641). Moreover, RG-7112induced tumor growth inhibition in solid tumor xenograft models and wasparticularly efficacious in in acute lymphoblastic leukemia (ALL)xenograft models with mixed-lineage leukemia (MLL) rearrangement, (Carolet al., Pediatric Blood and Cancer (2013) 60(4):633-641). Additionally,the antiproliferative and proapoptotic activity of RG7112 has beenobserved in human acute myeloid leukemia (AML) and human prostate tumorxenograft models harboring p53 wild-type (Tovar et al, Cancer Res (2013)73 (8): 2587-2597).

Accordingly, small molecule inhibitors of the MDM2 protein interactionsoffer an important approach towards cancer therapy, either as a singleagent, or in combination with a broad variety of anti-tumor therapiesand thus, there is the need for further MDM2 inhibitors which can beuseful in the treatment of cancer.

The following prior art documents disclose spiro oxindole compounds asinhibitors of MDM2-p53interaction:

WO 2007/104664; WO 2007/104714; WO 2008/141917; WO 2008/141975; WO2009/077357; WO 2009/080488; WO 2010/084097; WO 2010/121995; WO2011/067185; WO 2011/101297; WO 2011/134925; WO 2012/038307; WO2012/022707; WO 2012/116989; WO 2006/091646; WO 2008/036168; WO2011/060049; WO 2012/065022; WO 2012/155066; WO 2010/028862; WO2011/153509, WO 2012/121361, WO 2015/155332, WO 2016/001376 and WO2016/026937.

The aim of the present invention is to provide new compounds which canbe used for the prevention and/or treatment of a disease and/orcondition characterised by excessive or abnormal cell proliferation,especially a disease and/or condition wherein the inhibition of theinteraction between MDM2 and p53 is of therapeutic benefit.

The compounds according to the invention are characterised by a powerfulinhibitory effect on the interaction between MDM2 and p53 and in turn ahigh in vitro efficacy against tumour cells, e.g. osteosarcoma, ALLetc., which is mediated through the inhibition of the interactionbetween MDM2 and p53 and is the prerequisite for a correspondingefficacy in in vivo models and future patients. In addition to theinhibitory effect and cellular potency the compounds show good PKproperties and selectivity against p53 mutant cell lines. Furthermore,they have good metabolic stability which is a pivotal requirement for anactive pharmaceutical ingredient to reach its place of action and allowfor a long-lasting efficacy. Finally, and in contrast to many compoundsknown in the prior art, the compounds have good chemical stability, i.e.they are for example less prone to epimerisation, a problem identifiedfor many known representatives of spiro oxindoles in the prior art (seee.g. Zhao et al. J. Am. Chem. Soc 2013, 135, 7223-7234; Shu et al. Org.Process Res. Dev. 2013, 17, 247-256; WO 2012/065022). It is alsoemphasized that building up the scaffolds of compounds (I), i.e. thescaffolds of each subgroup (Ia), (Ib) and (Ic), is in itselfunprecedented and needs highly sophisticated synthetic approaches toobtain these compounds of high structural complexity.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that, surprisingly, compounds of formula (I)wherein the groups R¹ to R⁴, R⁷, A, D, E, F, V, W, X, Y, n, r and q havethe meanings given hereinafter act as inhibitors of the interaction ofspecific proteins which are involved in controlling cell proliferation.Thus, the compounds according to the invention may be used for examplefor the treatment of diseases connected with this protein-proteininteraction and characterised by excessive or abnormal cellproliferation.

The present invention therefore relates to a compound of formula (I)

[A0]

R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl;

-   -   each R^(b1) is independently selected from among —OR^(c1),        —NR^(c1)R^(c1), halogen, —CN, —C(O)R^(c1), —C(O)OR^(c1),        —C(O)NR^(c1)R^(c1), —S(O)₂R^(c1), —S(O)₂NR^(c1)R^(c1),        —NHC(O)R^(c1), —N(C₁₋₄alkyl)C(O)R^(c1) and the bivalent        substituent ═O, while ═O may only be a substituent in        non-aromatic ring systems;    -   each R^(c1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d1) and/or R^(e1), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1), —N(C₁₋₄alkyl)C(O)R^(e1) and the bivalent        substituent ═O, while ═O may only be a substituent in        non-aromatic ring systems;    -   each R^(e1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f1) and/or R^(g1), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(f1) is independently selected from among —OR^(g1),        —NR^(g1)R^(g1), halogen, —CN, —C(O)R^(g1), —C(O)OR^(g1),        —C(O)NR^(g1)R^(g1), —S(O)₂R^(g1), —S(O)₂NR^(g1)R^(g1),        —NHC(O)R^(g1), —N(C₁₋₄alkyl)C(O)R^(g1) and the bivalent        substituent ═O, while ═O may only be a substituent in        non-aromatic ring systems;    -   each R^(g1) is independently selected from among hydrogen,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;

[B0]

R² and R³, each independently, is selected from among hydrogen,C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl,wherein said C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl is optionally substituted by one or more, identical ordifferent R^(b)2 and/or R^(c2);

-   -   each R^(b2) is independently selected from among —OR^(c2),        —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2), —C(O)OR^(c2),        —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),        —NHC(O)R^(c2), —N(C₁₋₄alkyl)C(O)R^(c2) and the bivalent        substituent ═O, while ═O may only be a substituent in        non-aromatic ring systems;    -   each R^(c2) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d2) and/or R^(e2), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d2) is independently selected from among —OR^(e2),        —NR^(e2)R^(e2), halogen, —CN, —C(O)R^(e2), —C(O)OR^(e2),        —C(O)NR^(e2)R^(e2), —S(O)₂R^(e2), —S(O)₂NR^(e2)R^(e2),        —NHC(O)R^(e2), —N(C₁₋₄alkyl)C(O)R^(e2) and the bivalent        substituent ═O, while ═O may only be a substituent in        non-aromatic ring systems;    -   each R^(e2) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl;

[C0]

A is selected from among phenyl and 5-6 membered heteroaryl if F iscarbon or

A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is a group, optionally        substituted by one or more, identical or different R^(b4) and/or        R^(c4), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl;    -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4), —S(O)₂R^(c4),        —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4), —N(C₁₋₄alkyl)SO₂R^(c4),        —NHC(O)R^(c4), —N(C₁₋₄alkyl)C(O)R^(c4) and the bivalent        substituent ═O, while ═O may only be a substituent in        non-aromatic ring systems;    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d4) is independently selected from among —OR^(e4),        —NR^(e4)R^(e4), halogen, —CN, —C(O)R^(e4), —C(O)OR^(e4),        —C(O)NR^(e4)R^(e4), —C(O)NR^(g4)OR^(e4), —S(O)₂R^(e4),        —S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4), —N(C₁₋₄alkyl)C(O)R^(e4) and        the bivalent substituent ═O, while ═O may only be a substituent        in non-aromatic ring systems;    -   each R^(e4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f4) and/or R^(g4), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(f4) is independently selected from among —OR^(g4),        —NR^(g4)R^(g4), halogen, —CN, —C(O)R^(g4), —C(O)OR^(g4),        —C(O)NR^(g4)R^(g4), —C(O)NR^(g4)OR^(g4), —S(O)₂R^(g4),        —S(O)₂NR^(g4)R^(g4), —NHC(O)R^(g4), —N(C₁₋₄alkyl)C(O)R^(g4) and        the bivalent substituent ═O, while ═O may only be a substituent        in non-aromatic ring systems;    -   each R^(g4) is independently selected from among hydrogen,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;

r denotes the number 0, 1, 2 or 3;

[D0]

n denotes the number 1, 2 or 3;

[E0]

each R⁷ is independently selected from among halogen, C₁₋₄alkyl, —CN,C₁₋₄haloalkyl, —OC₁₋₄alkyl and —OC₁₋₄haloalkyl;

q denotes the number 0, 1, 2 or 3;

[F0]

W, X and Y is each independently selected from —N═ and —CH═

with the proviso that the hydrogen in each —CH═ may be replaced by asubstituent R⁷ if present and that a maximum of two of W, X and Y can be—N═;

[G0]

V is oxygen or sulfur;

[H0]

D is nitrogen, E is carbon and F is carbon; or

D is carbon, E is nitrogen and F is carbon; or

D is carbon, E is carbon and F is nitrogen;

or a salt thereof.

In one aspect the invention relates to a compound of formula (Ia)

or a salt thereof.

In one aspect the invention relates to a compound of formula (Ib)

or a salt thereof.

In one aspect the invention relates to a compound of formula (Ic)

or a salt thereof.

In one aspect the invention relates to a compound of formula (Ia*)

or a salt thereof.

In one aspect the invention relates to a compound of formula (Ib*)

or a salt thereof.

In one aspect the invention relates to a compound of formula (Ic*)

or a salt thereof.

It is to be understood that compounds (Ia), (Ib) and (Ic) each are asubset of compounds (I) and that whenever the term “compound(s) (I)” isused this also includes compound(s) (Ia), (Ib) and (Ic) unless statedotherwise.

It is to be understood that compounds (Ia*), (Ib*) and (Ic*) each are asubset of compounds (Ia), (Ib) and (Ic), respectively, and that whenever(Ia), (Ib) or (Ic) is used this also includes compound(s) (Ia*), (Ib*)and (Ic*), respectively, unless stated otherwise.

In another aspect [A1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl;

-   -   each R^(b1) is independently selected from among —OR^(c1),        —NR^(c1)R^(c1), halogen, —CN, —C(O)R^(c1), —C(O)OR^(c1),        —C(O)NR^(c1)R^(c1), —S(O)₂R^(c1), —S(O)₂NR^(c1)R^(c1),        —NHC(O)R^(c1) and —N(C₁₋₄alkyl)C(O)R^(c1);    -   each R^(c1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d1) and/or R^(e1), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1);    -   each R^(e1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f1) and/or R^(g1), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(f1) is independently selected from among —OR^(g1),        —NR^(g1)R^(g1), halogen, —CN, —C(O)R^(g1), —C(O)OR^(g1),        —C(O)NR^(g1)R^(g1), —S(O)₂R^(g1), —S(O)₂NR^(g1)R^(g1),        —NHC(O)R^(g1) and —N(C₁₋₄alkyl)C(O)R^(g1);    -   each R^(g1) is independently selected from among hydrogen,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;    -   or a salt thereof.

In another aspect [A2] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆haloalkyl and C₃₋₇cycloalkyl;

-   -   each R^(b1) is independently selected from among —OR^(c1),        —NR^(c1)R^(c1), halogen, —CN, —C(O)R^(c1), —C(O)OR^(c1),        —C(O)NR^(c1)R^(c1), —S(O)₂R^(c1), —S(O)₂NR^(c1)R^(c1),        —NHC(O)R^(c1) and —N(C₁₋₄alkyl)C(O)R^(c1);    -   each R^(c1) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d1) and/or R^(e1), selected from among C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d1) is independently selected from among —OR^(e1),        —NR^(e1)R^(e1), halogen, —CN, —C(O)R^(e1), —C(O)OR^(e1),        —C(O)NR^(e1)R^(e1), —S(O)₂R^(e1), —S(O)₂NR^(e1)R^(e1),        —NHC(O)R^(e1) and —N(C₁₋₄alkyl)C(O)R^(e1);    -   each R^(e1) independently of one another is selected from among        hydrogen, C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₃₋₇cycloalkyl,        C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 membered        heterocyclyl;

or a salt thereof.

In another aspect [A3] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆haloalkyl and C₃₋₇cycloalkyl;

-   -   each R^(b1) is independently selected from among —OR^(c1),        halogen and —S(O)₂R^(c1);    -   each R^(c1) independently of one another is a group, optionally        substituted by one or more, identical or different R^(d1) and/or        R^(e1), selected from among C₁₋₆alkyl, C₃₋₇cycloalkyl, C₆₋₁₀aryl        and 3-10 membered heterocyclyl;    -   each R^(d1) is independently selected from among —OR^(e1), —CN        and halogen;    -   each R^(e1) independently of one another is C₁₋₆alkyl or        C₁₋₆alkyl-O—C₁₋₆alkyl;

or a salt thereof.

In another aspect [A4] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl and C₁₋₆haloalkyl;

-   -   each R^(b1) is independently selected from among —OR^(c1) and        —S(O)₂R^(c1);    -   each R^(c1) independently of one another is a group, optionally        substituted by one or more, identical or different R^(d1) and/or        R^(e1), selected from among C₁₋₆alkyl, C₃₋₇cycloalkyl and        C₆₋₁₀aryl;    -   each R^(d1) is independently selected from among —OR^(e1), —CN        and halogen;    -   each R^(e1) independently of one another is C₁₋₆alkyl or        C₁₋₆alkyl-O—C₁₋₆alkyl;

or a salt thereof.

In another aspect [A5] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is a group, optionally substituted by one or more, identical ordifferent R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl,C₂₋₆alkenyl and C₁₋₆haloalkyl;

-   -   each R^(b1) is independently selected from among —OR^(c1) and        —S(O)₂R^(c1);    -   each R^(c1) independently of one another is a group, optionally        substituted by one or more, identical or different R^(d1) and/or        R^(e1), selected from among C₁₋₆alkyl, C₃₋₇cycloalkyl and        phenyl;    -   each R^(d1) is independently selected from among —OR^(e1), —CN        and halogen;    -   each R^(e1) independently of one another is C₁₋₆alkyl or        C₁₋₆alkyl-O—C₁₋₆-alkyl;

or a salt thereof.

In another aspect [A6] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is selected from among C₁₋₆alkyl, C₃₋₇cycloalkyl-C₁₋₆alkyl andC₂₋₆alkenyl;

or a salt thereof.

In another aspect [A7] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is C₃₋₇cycloalkyl-C₁₋₆-alkyl;

or a salt thereof.

In another aspect [A8] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R¹ is cyclopropylmethyl;

or a salt thereof.

In another aspect [B1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

R² and R³, each independently, is selected from among hydrogen,C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl,wherein said C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl is optionally substituted by one or more, identical ordifferent R^(b2) and/or R^(c2);

-   -   each R^(b2) is independently selected from among —OR^(c2),        —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2), —C(O)OR^(c2),        —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),        —NHC(O)R^(c2) and —N(C₁₋₄alkyl)C(O)R^(c2);    -   each R^(c2) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d2) and/or R^(e2), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d2) is independently selected from among —OR^(e2),        —NR^(e2)R^(e2), halogen, —CN, —C(O)R^(e2), —C(O)OR^(e2),        —C(O)NR^(e2)R^(e2), —S(O)₂R^(e2), —S(O)₂NR^(e2)R^(e2),        —NHC(O)R^(e2) and —N(C₁₋₄alkyl)C(O)R^(e2);    -   each R^(e2) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl;

or a salt thereof.

In another aspect [B2] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

one of R² and R³ is hydrogen and the other is selected from among phenyland 5-6 membered heteroaryl, wherein said phenyl and 5-6 memberedheteroaryl is optionally substituted by one or more, identical ordifferent R^(b2) and/or R^(c2);

-   -   each R^(b2) is independently selected from among —OR^(c2),        —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2), —C(O)OR^(c2),        —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),        —NHC(O)R^(c2) and —N(C₁₋₄alkyl)C(O)R^(c2);    -   each R^(c2) independently of one another denotes hydrogen or a        group selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, phenyl, 5-6        membered heteroaryl and 3-7 membered heterocyclyl;

or a salt thereof.

In another aspect [B3] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

one of R² and R³ is hydrogen and the other is selected from among phenyland 5-6 membered heteroaryl, wherein said phenyl and 5-6 memberedheteroaryl is optionally substituted by one or more, identical ordifferent substituents selected from among —OC₁₋₆alkyl, halogen,C₁₋₆alkyl and C₁₋₆haloalkyl;

or a salt thereof.

In another aspect [B4] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

one of R² and R³ is hydrogen and the other is selected from amongphenyl, thienyl and pyridyl, wherein said phenyl, thienyl and pyridyl isoptionally substituted by one or more, identical or differentsubstituents selected from among —OC₁₋₆alkyl, halogen, C₁₋₆alkyl andC₁₋₆haloalkyl;

or a salt thereof.

In another aspect [B5] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

one of R² and R³ is hydrogen and the other is selected from among3-chloro phenyl, 3-chloro-2-fluoro phenyl and 3-bromo 2-fluoro phenyl;

or a salt thereof.

In further aspects [B6], [B7], [B8], [B9], [B10] and [B11] the inventionrelates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or(Ic*) with structural aspects [B0], [B1], [B2] [B3], [B4] and [B5],wherein

R³ is hydrogen;

or a salt thereof.

In further aspects [B12], [B13], [B14], [B15], [B16] and [B17] theinvention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) with structural aspects [B0], [B1], [B2] [B3], [B4] and[B5], wherein

R² is hydrogen;

or a salt thereof.

In another aspect [C1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

A is selected from among phenyl and 5-6 membered heteroaryl if F iscarbon or

A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is a group, optionally        substituted by one or more, identical or different R^(b4) and/or        R^(c4), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl;    -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4), —S(O)₂R^(c4),        —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4), —N(C₁₋₄alkyl)SO₂R^(c4),        —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)R^(c4);    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(d4) is independently selected from among —OR^(e4),        —NR^(e4)R^(e4), halogen, —CN, —C(O)R^(e4), —C(O)OR^(e4),        —C(O)NR^(e4)R^(e4), —C(O)NR^(g4)OR^(e4), —S(O)₂R^(e4),        —S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4) and —N(C₁₋₄alkyl)C(O)R^(e4);    -   each R^(e4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f4) and/or R^(g4), selected from among C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,        C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10        membered heterocyclyl;    -   each R^(f4) is independently selected from among —OR^(g4),        —NR^(g4)R^(g4), halogen, —CN, —C(O)R^(g4), —C(O)OR^(g4),        —C(O)NR^(g4)R^(g4), —C(O)NR^(g4)OR^(g4), —S(O)₂R^(g4),        —S(O)₂NR^(g4)R^(g4), —NHC(O)R^(g4) and —N(C₁₋₄alkyl)C(O)R^(g4);    -   each R^(g4) is independently selected from among hydrogen,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

In another aspect [C2] the invention relates to a compound of formula(I), (Ia), (Ib), (Ia*) or (Ib*), wherein

A is phenyl and F is carbon;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is a group, optionally        substituted by one or more, identical or different R^(b4) and/or        R^(c4), selected from among C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₇cycloalkyl and 3-10 membered heterocyclyl;    -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4), —S(O)₂R^(c4) and        —NHC(O)R⁴;    -   each R^(c4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₇cycloalkyl and 3-10 membered heterocyclyl;    -   each R^(d4) is independently selected from among —OR^(e4),        NR^(e4)R^(e4) and —S(O)₂R^(e4);    -   each R^(e4) independently of one another denotes hydrogen or a        group, optionally substituted by one or more, identical or        different R^(f4) and/or R^(g4), selected from among C₁₋₆alkyl        and 3-10 membered heterocyclyl;    -   each R^(f4) is —OR^(g4);    -   each R^(g4) is independently selected from among hydrogen and        C₁₋₆alkyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

In another aspect [C3] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

A is selected from among phenyl and 5-6 membered heteroaryl if F iscarbon or

A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is a group, optionally        substituted by one or more, identical or different R^(b4) and/or        R^(c4), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10        membered heteroaryl and 3-10 membered heterocyclyl;    -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NHOR^(c4), —S(O)₂R^(c4),        —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4), —N(C₁₋₄alkyl)SO₂R^(c4),        —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)R^(c4);    -   each R^(c4) independently of one another is selected from among        hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl and 3-10 membered heterocyclyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

In another aspect [C4] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

A is selected from among phenyl and pyridyl if F is carbon or

A is pyridyl if F is nitrogen;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is C₁₋₆alkyl optionally        substituted by one or more, identical or different R^(b4);    -   each R^(b4) is independently selected from among —OR^(c4),        —NR^(c4)R^(c4), halogen, —CN, —C(O)R^(c4), —C(O)OR^(c4),        —C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4), —S(O)₂R^(c4),        —S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4), —N(C₁₋₄alkyl)SO₂R^(c4),        —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)R^(c4);    -   each R^(c4) independently of one another is selected from among        hydrogen and C₁₋₆alkyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

In another aspect [C5] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

A is selected from among phenyl and pyridyl if F is carbon or

A is pyridyl if F is nitrogen;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is C₁₋₆alkyl optionally        substituted by one or more, identical or different R^(b4);    -   each R^(b4) is independently selected from among —OR^(c4),        halogen, —CN, —C(O)OR^(c4), —C(O)NR^(c4)R^(c4) and —S(O)₂R^(c4);    -   each R^(c4) independently of one another is selected from among        hydrogen and C₁₋₆alkyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

In another aspect [C6] the invention relates to a compound of formula(I), (Ia), (Ib), (Ia*) or (Ib*), wherein

A is phenyl and F is carbon;

each R⁴ is independently selected from among R^(a4) and R^(b4);

-   -   each R^(a4) independently of one another is C₁₋₆alkyl optionally        substituted by one or more, identical or different R^(b4);    -   each R^(b4) is independently selected from among —OR^(c4),        halogen, —CN, —C(O)OR^(c4), —C(O)NR^(c4)R^(c4) and —S(O)₂R^(c4);    -   each R^(c4) independently of one another is selected from among        hydrogen and C₁₋₆alkyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

In further aspects [C7], [C8], [C9], [C10], [C11], [C12] and [C13] theinvention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) with structural aspects [C0], [C1], [C2], [C3], [C4],[C5] and [C6], wherein

r denotes the number 1 or 2;

or a salt thereof.

In another aspect [C14] the invention relates to a compound of formula(I), (Ia), (Ib), (Ia*) or (Ib*), wherein

A together with the r substituents R⁴ is

R⁸ is selected from among hydrogen, C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CN, —C(O)OH, —C(O)OC₁₋₆alkyl, —C(O)NH₂, —C(O)NHC₁₋₆alkyl,—C(O)N(C₁₋₆alkyl)₂ and —S(O)₂C₁₋₆alkyl;

R⁹ is selected from among hydrogen, C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CN, —C(O)OH, —C(O)OC₁₋₆alkyl, —C(O)NH₂, —C(O)NHC₁₋₆alkyl,—C(O)N(C₁₋₆alkyl)₂ and —S(O)₂C₁₋₆alkyl;

R¹⁰ is selected from among hydrogen, C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CN, —C(O)OH, —C(O)OC₁₋₆alkyl, —C(O)NH₂, —C(O)NHC₁₋₆alkyl,—C(O)N(C₁₋₆alkyl)₂ and —S(O)₂C₁₋₆alkyl;

with the proviso that at least one of R⁸ to R¹⁰ but not all of R⁸ to R¹⁰is/are hydrogen;

or a salt thereof.

In another aspect [C15] the invention relates to a compound of formula(I), (Ia), (Ib), (Ia*) or (Ib*), wherein

A together with the r substituents R⁴ is

R⁸ is —C(O)OH;

one of R⁹ and R¹⁰ is C₁₋₄alkyl and the other is hydrogen;

or a salt thereof.

In another aspect [D1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

n denotes the number 1 or 2;

or a salt thereof.

In another aspect [D2] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

n is 1;

or a salt thereof.

In another aspect [D3] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

n is 2;

or a salt thereof.

In another aspect [E1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

each R⁷ independently is halogen or —CN and q is 1 or 2;

or a salt thereof.

In another aspect [E2] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

each R⁷ independently is chlorine or fluorine and q is 1 or 2;

or a salt thereof.

In another aspect [F1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

W, X and Y are —CH═ with the proviso that the hydrogen in each —CH═ maybe replaced by a substituent R⁷ if present;

or a salt thereof.

In another aspect [EF1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

the 6-membered ring comprising W, X and Y together with the qsubstituents R⁷ has a substructure selected from among (i) and (ii)

or a salt thereof.

In another aspect [G1] the invention relates to a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*), wherein

V is oxygen;

or a salt thereof.

All the above-mentioned structural aspects A to A8, B1 to B17, C1 toC15, D1 to D3, E1 and E2, F1, G1 and E1 are preferred embodiments of thecorresponding aspects A0, B0, C0, D0, E0, F0, EF0 and G0, respectively,wherein EF0 (EF) represents the combination of E0 (E) and F0 (F). Thestructural aspects A0 to A8, B0 to B17, C0 to C15, D0 to D3, E0 to E2,F0 and F1, EF0 and EF, and G0 and G1 relating to different molecularparts of the compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and (Ic*)according to the invention may be permutated with one another as desiredin combinations ABCDEFG, so as to obtain preferred compounds (I), (Ia),(Ib), (Ic), (Ia*), (Ib*) and (Ic*) (aspects E and F can be replaced bycombination aspect EF). Each combination ABCDEFG represents and definesindividual embodiments or generic subsets of compounds according to theinvention.

Preferred embodiments of the invention with structure (Ia) are examplecompounds Ia-1 to Ia-57.

Preferred embodiments of the invention with structure (Ib) are examplecompounds Ib-1 to Ib-254.

Preferred embodiments of the invention with structure (Ic) are examplecompounds Ic-1 to Ic-38.

All synthetic intermediates generically defined as well es specificallydisclosed herein and their salts are also part of the invention.

In a further aspect the invention also relates to syntheticintermediates of formula B-3 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R², R³, R⁷, V, W, X, Y, q and n in B-3correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R³, [D0] for n, [E0] for R⁷/q,[F0] for W/X/Y and [G0] for V. R is a carboxyl protecting group, e.g.C₁₋₆alkyl or t-Bu.

Preferred intermediates B-3 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-3 have structural aspects selected from [B0] to [B17] for R²/R³, [D0]to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and[G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether. Thesestructural aspects (including definitions of R) may be permutated withone another as desired in combinations BDEFGR, so as to obtain preferredintermediates B-3 (aspects E and F can be replaced by combination aspectEF). Each combination BDEFGR represents and defines individualembodiments or generic subsets of intermediates B-3.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-3 or their salts (and the various embodimentsand sub-groups as described and/or defined herein) in the synthesis ofcompounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-4 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R¹, R², R³, R⁷, V, W, X, Y, q and n in B-4correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [A0] for R¹, [B0] for R²/R, [D0] for n, [E0]for R/q, [F0] for W/X/Y and [G0] for V. R is a carboxyl protectinggroup, e.g. C₁₋₆alkyl or t-Bu.

Preferred intermediates B-4 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-4 have structural aspects selected from [A0] to [A8] for R¹, [B0] to[B17] for R²/R³, [D0] to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and[F1] for W/X/Y, [G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Yaltogether. These structural aspects (including definitions of R) may bepermutated with one another as desired in combinations ABDEFGR, so as toobtain preferred intermediates B-4 (aspects E and F can be replaced bycombination aspect EF). Each combination ABDEFGR represents and definesindividual embodiments or generic subsets of intermediates B-4.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-4 or their salts (and the various embodimentsand sub-groups as described and/or defined herein) in the synthesis ofcompounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-7 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R¹, R², R, R⁷, V, W, X, Y, q and n in B-7correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [A0] for R¹, [B0] for R²/R, [D0] for n, [E0]for R/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-7 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-7 have structural aspects selected from [A0] to [A8] for R¹, [B0] to[B17] for R²/R³, [D0] to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and[F1] for W/X/Y, [G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Yaltogether. These structural aspects may be permutated with one anotheras desired in combinations ABDEFG, so as to obtain preferredintermediates B-7 (aspects E and F can be replaced by combination aspectEF). Each combination ABDEFG represents and defines individualembodiments or generic subsets of intermediates B-7.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-7 or their salts (and the various embodimentsand sub-groups as described and/or defined herein) in the synthesis ofcompounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-6 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R², R³, R⁷, V, W, X, Y, q and n in B-6correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R, [D0] for n, [E0] for R⁷/q,[F0] for W/X/Y and [G0] for V.

Preferred intermediates B-6 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-6 have structural aspects selected from [B0] to [B17] for R²/R, [D0]to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and[G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether. Thesestructural aspects may be permutated with one another as desired incombinations BDEFG, so as to obtain preferred intermediates B-6 (aspectsE and F can be replaced by combination aspect EF). Each combinationBDEFG represents and defines individual embodiments or generic subsetsof intermediates B-6.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-6 or their salts (and the various embodimentsand sub-groups as described and/or defined herein) in the synthesis ofcompounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-8 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R¹, R², R, R⁷, V, W, X, Y, q and n in B-8correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [A0] for R¹, [B0] for R²/R³, [D0] for n, [E0]for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-8 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-8 have structural aspects selected from [A0] to [A8] for R¹, [B0] to[B17] for R²/R³, [D0] to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and[F1] for W/X/Y, [G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Yaltogether. These structural aspects may be permutated with one anotheras desired in combinations ABDEFG, so as to obtain preferredintermediates B-8 (aspects E and F can be replaced by combination aspectEF). Each combination ABDEFG represents and defines individualembodiments or generic subsets of intermediates B-8.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-8 or their salts (and the various embodimentsand sub-groups as described and/or defined herein) in the synthesis ofcompounds (Ia) and (a*).

In a further aspect the invention also relates to syntheticintermediates of formula B-10 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R¹, R², R³, R⁴, R⁷, A, V, W, X, Y, r, q and nin B-10 correspond to those as given for compound (I), (Ia), (Ib), (Ic),(Ia*), (Ib*) or (Ic*) above, i.e. [A0] for R¹, [B0] for R²/R³, [C0] forA/R⁴/r, [D0] for n, [E0] for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-10 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-10 have structural aspects selected from [A0] to [A8] for R¹, [B0] to[B17] for R²/R³, [C0] to [C15] for A/R⁴/r, [D0] to [D3] for n, [E0] to[E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and [G1] for V and [EF0]and [EF1] for R⁷/q/W/X/Y altogether. These structural aspects may bepermutated with one another as desired in combinations ABCDEFG, so as toobtain preferred intermediates B-10 (aspects E and F can be replaced bycombination aspect EF). Each combination ABCDEFG represents and definesindividual embodiments or generic subsets of intermediates B-10.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-10 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-11 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R¹, R², R³, R⁴, R⁷, A, V, W, X, Y, r, q and nin B-11 correspond to those as given for compound (I), (Ia), (Ib), (Ic),(Ia*), (Ib*) or (Ic*) above, i.e. [A0] for R¹, [B0] for R²/R³, [C0] forA/R⁴/r, [D0] for n, [E0] for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-11 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-11 have structural aspects selected from [A0] to [A8] for R¹, [B0] to[B17] for R²/R³, [C0] to [C15] for A/R⁴/r, [D0] to [D3] for n, [E0] to[E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and [G1] for V and [EF0]and [EF1] for R⁷/q/W/X/Y altogether. These structural aspects may bepermutated with one another as desired in combinations ABCDEFG, so as toobtain preferred intermediates B-11 (aspects E and F can be replaced bycombination aspect EF). Each combination ABCDEFG represents and definesindividual embodiments or generic subsets of intermediates B-11.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-11 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-12 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R¹, R², R³, R⁴, R⁷, A, V, W, X, Y, r, q and nin B-12 correspond to those as given for compound (I), (Ia), (Ib), (Ic),(Ia*), (Ib*) or (Ic*) above, i.e. [A0] for R¹, [B0] for R²/R³, [C0] forA/R⁴/r, [D0] for n, [E0] for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-12 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-12 have structural aspects selected from [A0] to [A8] for R¹, [B0] to[B17] for R²/R³, [C0] to [C15] for A/R⁴/r, [D0] to [D3] for n, [E0] to[E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and [G1] for V and [EF0]and [EF1] for R⁷/q/W/X/Y altogether. These structural aspects may bepermutated with one another as desired in combinations ABCDEFG, so as toobtain preferred intermediates B-12 (aspects E and F can be replaced bycombination aspect EF). Each combination ABCDEFG represents and definesindividual embodiments or generic subsets of intermediates B-12.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-12 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to syntheticintermediates of formula B-16 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of group R⁴, A and r in B-16 correspond to those asgiven for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) above,i.e. [C0] for A/R⁴/r.

Preferred intermediates B-16 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-16 have structural aspects selected from [C0] to [C15] for A/R⁴/r eachdefining individual embodiments or generic subsets of intermediatesB-16. Preferred intermediates B-16 are selected from intermediates B-16ato B-16f (see table 15-2 below), including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-16 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-16

or a salt thereof,comprising bromination of a compound of formula B-15

or a salt thereof, whereinthe reaction is performed in a solvent with a source of electrophilicbromine in the presence of a palladium catalyst and an acidic additive,and R⁴, A and r is as hereinbefore defined.

STEP A Embodiments/Conditions for STEP A

The solvent to be chosen can be an organic solvent, preferably chosenfrom the group consisting of a carboxylic acid, a carboxylic ester, analkane and an aromatic solvent, or a mixture thereof. More preferablythe solvent is chosen from the group consisting of AcOH, nBuOAc, iPrOAc,MCH, nHep, toluene and xylol (or a mixture thereof, e.g. nBuOAc/AcOH(9:1), iPrOAc/AcOH (9:1), toluene/AcOH (9:1)). Most preferred is AcOH.

The source of electrophilic bromine can, e.g., be selected from thegroup consisting of NBS, N-bromosaccharine and1,3-dibromo-5,5-dimethylhydantoine. Preferably, NBS is chosen as sourceof electrophilic bromine.

Preferably, the palladium catalyst to be used can be a Pd(II) catalyst,e.g., a Pd(II) catalyst chosen from the group consisting of Pd(OAc)₂ andPd(OC(O)CF₃)₂. The preferred Pd(II) catalyst is Pd(OAc)₂.

As far as the acidic additive is concerned this is preferentially anaromatic acid, preferably an aromatic sulfonic acid. Most preferredacidic additive is TsOH or a hydrate thereof.

The reaction can be performed at a temperature range of about 70° C. toabout 100° C., preferably at about 60° C. to about 90° C. Mostpreferably, the temperature range is about 60° C. to about 80° C.

Preferred intermediates B-16 which may be synthesized by this method areselected from any one of intermediates B-16a to B-16f (see table 15-2below), including their salts.

The advantage of the bromination step as described herein is itsefficiency and high yield due to almost complete control ofregiochemistry for the subsequent installation of the linker betweensubstituted ring system A and the isatin (oxindole) scaffold which isalso positively influenced by the anilide protecting group, thetemperature range applied and the choice of AcOH as reaction solvent. Inaddition, the use of NBS is process friendly.

In a further aspect the invention also relates to syntheticintermediates of formula B-17 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of group R⁴, A and r in B-17 correspond to those asgiven for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) above,i.e. [C0] for A/R⁴/r.

Preferred intermediates B-17 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-17 have structural aspects selected from [C0] to [C15] for A/R⁴/r eachdefining individual embodiments or generic subsets of intermediatesB-17. Preferred intermediates B-17 are selected from intermediates B-17ato B-17f (see table 15-3 below), including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-17 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-17

or a salt thereof,comprising reacting a compound of formula B-16

or a salt thereof,with prop-2-ynyl-carbamic acid tert-butyl ester

whereinthe reaction is performed in a solvent in the presence of a palladiumcatalyst, a ligand, a base and, optionally, a copper co-catalyst, andR⁴, A and r is as hereinbefore defined.

STEP B Embodiments/Conditions for STEP B

The solvent to be chosen can be an organic solvent, preferably chosenfrom the group consisting of DMSO, DMF, ACN, THF, dioxane, NMP, iPrOAc,toluene, nBuOH, or a mixture thereof. Most preferred is DMSO.

Preferably, the palladium catalyst to be used is a Pd(II) or a Pd(0)catalyst, e.g., a palladium catalyst chosen from the group consisting ofPd(OAc)₂ and Pd₂(dba)₃. The preferred palladium catalyst is Pd₂(dba)₃.

The ligand to be used in the reaction is preferably an organophosphorouscompound, e.g. a ligand selected from the group consisting of[(tBu)₃PH]BF₄, RuPhos and Xphos. The preferred ligand to be used is[(tBu)₃PH]BF₄.

The copper co-catalyst, if present, preferably is a copper salt, morepreferably a Cu(I) salt, e.g. selected from the group consisting of CuI,CuCl and Cu₂O. The preferred copper co-catalyst is CuI.

The base to be used is preferably an organic base, more preferably anamine base, e.g. a secondary amine. Most preferred is the use of DIPA.

The reaction can be performed at a temperature range of about 20° C. toabout 70° C., preferably at about 20° C. to about 40° C. Mostpreferably, the temperature range is about 20° C. to about 30° C.

Preferred intermediates B-17 which may be synthesized by this method areselected from any one of intermediates B-17a to B-17f (see table 15-3below), including their salts.

In a further aspect the invention also relates to syntheticintermediates of formula B-18 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of group R⁴, A and r in B-18 correspond to those asgiven for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) above,i.e. [C0] for A/R⁴/r.

Preferred intermediates B-18 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-18 have structural aspects selected from [C0] to [C15] for A/R⁴/r eachdefining individual embodiments or generic subsets of intermediatesB-18. Preferred intermediates B-18 are selected from intermediates B-18ato B-181 (see tables 15-4 and 15-5 below), including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-18 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-18

or a salt thereof,comprising hydration and deprotection of a compound of formula B-17

or a salt thereof, whereinthe hydration step is performed in the presence of a palladium catalystin a solvent and the deprotection step is performed in the presence ofan acid, and R⁴, A and r is as hereinbefore defined.

STEP C Embodiments/Conditions for STEP C

The solvent to be chosen can be an organic solvent, preferably acarboxylic acid. Most preferred is AcOH.

Preferably, the palladium catalyst to be used is a Pd(II) catalyst,e.g., a Pd(II) catalyst chosen from the group consisting of Pd(OAc)₂,PdCl₂ and Pd(OC(O)CF₃)₂. The preferred Pd(II) catalyst is Pd(OAc)₂.

The acid to be used in the deprotection step is preferably an aqueousinorganic acid, e.g. selected from the group consisting of aqueous HCl,HBr and H₂SO₄. Most preferred is aqueous HCl.

The hydration step can be performed at a temperature range of about 20°C. to about 80° C., preferably at a range of about 20° C. to about 50°C. Most preferred is a range of about 20° C. to about 30° C.

The deprotection step can be performed at a temperature range of about20° C. to about 80° C.

Preferred intermediates B-18 which may be synthesized by this method areselected from any one of intermediates B-18a to B-181 (see table 15-4and 15-5 below) and their salts.

The intermediate product obtained after the hydration step, i.e. B-18still bearing the acetyl and Boc protecting group, is also part of theinvention.

In a further aspect the invention also relates to syntheticintermediates of formula B-19 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R⁴, R⁷, A, V, W, X, Y, r and q in B-19correspond to those as given for compound (I), (Ia), (Ib), (Ic), (a*),(Ib*) or (Ic*) above, i.e. [C0] for A/R⁴/r, [E0] for R⁷/q, [F0] forW/X/Y and [G0] for V.

Preferred intermediates B-19 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-19 have structural aspects selected from [C0] to [C15] for A/R⁴/r,[E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and [G1] for V and[EF0] and [EF1] for R⁷/q/W/X/Y altogether. These structural aspects maybe permutated with one another as desired in combinations CEFG, so as toobtain preferred intermediates B-19 (aspects E and F can be replaced bycombination aspect EF).

Each combination CEFG represents and defines individual embodiments orgeneric subsets of intermediates B-19. Preferred intermediates B-19 areselected from intermediates B-19a to B-19f (see table 15-6 below),including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-19 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (a*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-19

or a salt thereof,comprising reacting a compound of formula B-18

or a salt thereof,with a compound of formula S-1

or a salt thereof,wherein the reaction is performed in a solvent in the presence of anacid and a base, and R⁴, R⁷, A, V, W, X, Y, r and q is as hereinbeforedefined.

STEP D Embodiments/Conditions for STEP D

The solvent to be chosen can be an organic solvent, preferably chosenfrom the group consisting of MeOH, DMF, ACN, NMP and THF, or a mixturethereof. Most preferred is a mixture of MeOH and DMF.

The acid to be used is preferably an organic acid, more preferably acarboxylic acid. Most preferred is the use of AcOH.

The base to be used is preferably an organic base, more preferably anamine base, e.g. a tertiary amine. The tertiary amine is preferablyselected from the group consisting of TEA, DIPEA andN-ethyl-dicyclohexyl amine. Most preferred is the use of TEA.

The reaction can be performed at a temperature range of about −10° C. toabout 50° C., preferably at about 10° C. to about 20° C.

Preferred intermediates B-19 which may be synthesized by this method areselected from any one of intermediates B-19a to B-191 (see table 15-6below) including their salts.

In a further aspect the invention also relates to syntheticintermediates of formula B-20 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, r and q in B-20correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [E0] forR⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-20 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-20 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y,[G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether. Thesestructural aspects may be permutated with one another as desired incombinations BCEFG, so as to obtain preferred intermediates B-20(aspects E and F can be replaced by combination aspect EF). Eachcombination BCEFG represents and defines individual embodiments orgeneric subsets of intermediates B-20. Preferred intermediates B-20 areselected from intermediates B-20a to B-20f (see table 15-7 below),including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-20 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (a*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-20

or a salt thereof,comprising reacting a compound of formula B-2

or a salt thereof,with a compound of formula B-19

or a salt thereof, whereinthe reaction is performed in a solvent in the presence of a base, andR², R³, R⁴, R⁷, A, V, W, X, Y, r and q is as hereinbefore defined.

STEP E Embodiments/Conditions for STEP E

The solvent to be chosen is an organic solvent or a mixture of anorganic solvent and water. Preferably, the organic solvent is selectedfrom the group consisting of MeTHF, dioxane, DCM, ACN, toluene,2-methyl-2-butanol and iPrOH, or a mixture thereof, or a mixture of theorganic solvent(s) with water. Most preferred is a mixture of tolueneand water.

The base to be used is preferably an organic base, more preferably anamine base. The amine base is preferably selected from the groupconsisting of N-methylpyrrolidine, N-ethylpyrrolidine,N-methylpiperidine, 1-(2-hydroxyethyl)-pyrrolidine, 3-quinuclidinol andDABCO. Most preferred is the use of N-methylpyrrolidine.

The reaction can be performed at a temperature range of about 35° C. toabout 110° C., preferably at about 40° C. to about 85° C.

Preferred intermediates B-20 which may be synthesized by this method areselected from any one of intermediates B-20a to B-20f (see table 15-7below) including their salts.

In a further aspect the invention also relates to a method for chiralseparation of a mixture comprising both enantiomers of an intermediateof formula B-20

comprising precipitating a salt of one enantiomer formed with a chiralacid.

Embodiments/conditions for chiral separation:

The chiral acid to be used is, e.g., preferably selected from among(+)-Di-O,O′-dibenzoyl-D-tartaric acid, (−)-Di-O,O′-dibenzoyl-L-tartaricacid, (+)-Di-O,O′-p-toluoyl-D-tartaric acid,(−)-Di-O,O′-p-toluoyl-L-tartaric acid, (1 S)-(+)-camphor-10-sulfonicacid, (1R)-(−)-camphor-10-sulfonic acid, (R)-(−)-mandelic acid,(S)-(+)-mandelic acid, L-pyroglutamic acid, D-pyroglutamic acidL-(+)-tartaric acid and D-(−)-tartaric acid. Most preferred is (1R)-(−)-and (1 S)-(+)-camphor-10-sulfonic acid. The salt of the enantiomer isprecipitated from a solution or suspension of compounds B-20 in anappropriate solvent, preferably ACN. Without wishing to be bound bytheory, it is assumed that the formation of labile acetonitrile solvatesof the precipitating camphor-10-sulfonic acid salt may be responsiblefor the resolution of racemic mixtures of the most preferred compounds.The salt precipitates selectively, i.e. one enantiomer precipitates as asalt of the chiral acid whereas the other enantiomer remains/issubstantially dissolved under the conditions applied. The freeenantiomer can be recovered from the salt by ion exchange. The methoddescribed hereinbefore can also be applied for the enrichment of oneenantiomer in relation to the other if complete separation can not beachieved or the steps can be repeated several times to achieve completeseparation. Separation means that the respective enantiomer/salt isobtained in a form that is substantially free of the other enantiomer.Preferably, the chiral acid is used in sub-stoichiometric amounts inrelation to the enantiomer being separated, i.e. preferably in a rangeof 0.5-0.9 eq. (about 0.6 eq. being most preferred). The totalconcentration of racemate in the solution/suspension before separationis preferably in a range of 50-150 g/L, about 100 g/L being mostpreferred.

Preferred chiral intermediates B-20 which may be separated from theirenantiomer by this method are selected from any one of intermediatesB-20g to B-20l (see table 15-7 below) including their salts.

In a further aspect the invention also relates to syntheticintermediates of formula B-21 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, r and q in B-21correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [E0] forR⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-21 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-21 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y,[G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether. Thesestructural aspects may be permutated with one another as desired incombinations BCEFG, so as to obtain preferred intermediates B-21(aspects E and F can be replaced by combination aspect EF). Eachcombination BCEFG represents and defines individual embodiments orgeneric subsets of intermediates B-21. Preferred intermediates B-21 areselected from intermediates B-21a to B-21f (see table 15-8 below),including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-21 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-21

or a salt thereof,comprising hydrogenating a compound of formula B-20,

or a salt thereof, whereinthe reaction is performed in a solvent in the presence of a Pt catalyst,and R², R³, R⁴, R⁷, A, V, W, X, Y, r and q is as hereinbefore defined.

Embodiments/Conditions for this Step:

The solvent to be chosen can be an organic solvent. Preferably, theorganic solvent is selected from the group consisting of MeTHF, THF,MeOH, nBuOAc and iPrOAc, or a mixture thereof. Most preferred is MeTHF.

Preferably, the Pt catalyst to be used is Pt/C.

The reaction can be performed at a temperature range of about 20° C. toabout 100° C., preferably at about 20° C. to about 30° C.

The H₂-pressure applied for hydrogenation is preferably in the range ofabout 20 bar to about 70 bar. Most preferred the H₂-pressure is in therange of about 60 bar to about 70 bar Preferred intermediates B-21 whichmay be synthesized by this method are selected from any one ofintermediates B-21a to B-21f (see table 15-8 below) including theirsalts.

In a further aspect the invention also relates to syntheticintermediates of formula B-22 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, r and q in B-22correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [E0] forR⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-22 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-22 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y,[G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether.

These structural aspects may be permutated with one another as desiredin combinations BCEFG, so as to obtain preferred intermediates B-22(aspects E and F can be replaced by combination aspect EF). Eachcombination BCEFG represents and defines individual embodiments orgeneric subsets of intermediates B-22. Preferred intermediates B-22 areselected from intermediates B-22a to B-22f (see table 15-8 below),including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-22 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-22

or a salt thereof,comprising hydrogenating a compound of formula B-21,

or a salt thereof, wherein

The reaction is performed in a solvent in the presence of a Pt catalystand a V catalyst, and R², R³, R⁴, R⁷, A, V, W, X, Y, r and q is ashereinbefore defined.

Embodiments/Conditions for this Step

The solvent to be chosen can be an organic solvent. Preferably, theorganic solvent is selected from the group consisting of MeTHF, THF,MeOH, nBuOAc and iPrOAc, or a mixture thereof. Most preferred is MeTHF.

Preferably, the Pt catalyst to be used is Pt/C.

Preferably, the V catalyst to be used is a V(IV) catalyst. Mostpreferred is VO(acac)₂.

The reaction can be performed at a temperature range of about 20° C. toabout 60° C., preferably at about 20° C. to about 30° C.

The H₂-pressure applied for hydrogenation is preferably in the range ofabout 3 to about 70 bar. Most preferred the H₂-pressure is in the rangeof about 60 bar to about 70 bar.

Preferred intermediates B-22 which may be synthesized by this method areselected from any one of intermediates B-22a to B-22f (see table 15-8below) including their salts.

In a further aspect the invention also relates to a method for chiralseparation of a mixture comprising both enantiomers of an intermediateof formula B-22

comprising precipitating a salt of one enantiomer formed with a chiralacid.

Embodiments/Conditions for Chiral Separation

The chiral acid to be used is, e.g., preferably selected from among(+)-Di-O,O′-dibenzoyl-D-tartaric acid, (−)-Di-O,O′-dibenzoyl-L-tartaricacid, (+)-Di-O,O′-p-toluoyl-D-tartaric acid,(−)-Di-O,O′-p-toluoyl-L-tartaric acid, (1 S)-(+)-camphor-10-sulfonicacid, (1R)-(−)-camphor-10-sulfonic acid, (R)-(−)-mandelic acid,(S)-(+)-mandelic acid, L-pyroglutamic acid, D-pyroglutamic acid,L-(+)-tartaric acid, D-(−)-tartaric acid, L-(+)-lactic acid andL-(+)-lactic acid. Most preferred is (+)-Di-O,O′-p-toluoyl-D-tartaricacid and (−)-Di-O,O′-p-toluoyl-L-tartaric acid. The salt of theenantiomer is precipitated from a solution or suspension of compoundsB-22 in an appropriate solvent, preferably ACN. The salt precipitatesselectively, i.e. one enantiomer precipitates as a salt of the chiralacid whereas the other enantiomer remains/is substantially dissolvedunder the conditions applied. The free enantiomer can be recovered fromthe salt by ion exchange. The method described hereinbefore can also beapplied for the enrichment of one enantiomer in relation to the other ifcomplete separation can not be achieved or the steps can be repeatedseveral times to achieve complete separation. Separation means that therespective enantiomer/salt is obtained in a form that is substantiallyfree of the other enantiomer. Preferably, the chiral acid is used insub-stoichiometric amounts in relation to the enantiomer beingseparated, i.e. preferably in a range of 0.5-1 eq. (1 eq. being mostpreferred). The total concentration of racemate in thesolution/suspension before separation is preferably in a range of 50-150g/L, about 100 g/L being most preferred.

Preferred chiral intermediates B-22 which may be separated from theirenantiomer by this method are selected from any one of intermediatesB-22a to B-22f (see table 15-7 below) including their salts.

In a further aspect the invention also relates to syntheticintermediates of formula B-23 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ia) and (Ia*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, r and q in B-23correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [E0] forR⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates B-23 are those which lead to preferred compounds(Ia) and (Ia*) according to the invention, i.e. preferred embodiments ofB-23 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y,[G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether. Thesestructural aspects may be permutated with one another as desired incombinations BCEFG, so as to obtain preferred intermediates B-23(aspects E and F can be replaced by combination aspect EF). Eachcombination BCEFG represents and defines individual embodiments orgeneric subsets of intermediates B-23. Preferred intermediates B-23 areselected from intermediates B-23a to B-23f (see table 15-9 below),including their salts.

In a further aspect the invention also relates to the use of syntheticintermediates of formula B-23 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ia) and (Ia*).

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-23

or a salt thereof,comprising oxidation of a compound of formula B-22,

or a salt thereof, whereinthe reaction is performed in a solvent in the presence of a catalyst andan oxidizing agent, and R², R³, R⁴, R⁷, A, V, W, X, Y, r and q is ashereinbefore defined.

Embodiments/Conditions for this Step

The solvent to be chosen is an organic solvent or a mixture of anorganic solvent and water. Preferably, the organic solvent is selectedfrom the group consisting of DCM and toluene, or a mixture thereof, or amixture of the organic solvent(s) with water. Most preferred is amixture of DCM and water.

The catalyst to be used can be a Mo-, V- or W-catalyst. Preferably, thecatalyst is selected from the group consisting of (NH₄)₂MoO₄, Na₂MoO₄,VO(acac)₂, MoO₂(acac)₂, Na₂WO₄*2H₂O. Most preferred is Na₂WO₄*2H₂O.

As far as the oxidizing agent is concerned H₂O₂ is preferably used, inparticular H₂O₂ in water.

The reaction can be performed at a temperature range of about 0° C. toabout 50° C., preferably at about 35° C. to about 40° C.

Preferred intermediates B-23 which may be synthesized by this method areselected from any one of intermediates B-23a to B-23f (see table 15-9below) including their salts.

Synthetic steps B-20+B-21, B-21+B-22 and B-22+B-23 can also be performedwith racemic intermediate B-20, B-21 and B-22, respectively (if chiralseparation of B-20 is not performed). Racemic B-21, B-22 and B-23 andthe corresponding reaction steps with the racemic intermediates are alsopart of the invention.

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-18 comprising STEP A ashereinbefore described (VARIANT 1). In a further aspect the inventionalso relates to a method for synthesizing an intermediate of formulaB-18 comprising STEP A and STEP B as hereinbefore described (VARIANT 2).In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-18 comprising STEP A and STEPB and STEP C as hereinbefore described (VARIANT 3). Syntheses accordingto VARIANTS 1 to 3 are advantageous over alternative approaches that maybe considered and allow for an improved overall synthetic efficiency andthrougput, lower costs and reduced solvents and waste.

In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-20 comprising STEP D ashereinbefore described (VARIANT 4). In a further aspect the inventionalso relates to a method for synthesizing an intermediate of formulaB-20 comprising STEP D and STEP E as hereinbefore described (VARIANT 5).In a further aspect the invention also relates to a method forsynthesizing an intermediate of formula B-20 comprising STEP A and STEPB and STEP C and STEP D and STEP E as hereinbefore described (VARIANT6).

In a further aspect the invention also relates to a method forsynthesizing a compound of formula (Ia) and (Ia*) comprising a variantselected from VARIANT 1 to 6.

All STEPS as referred to hereinbefore include all embodiments/conditionsof how the STEPS can be performed as disclosed hereinbefore.

In a further aspect the invention also relates to syntheticintermediates of formula A-12 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R³, R⁷, V, W, X, Y, n and q in A-12correspond to those as given for compound (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*) above, i.e. [B0] for R²/R³, [D0] for n, [E0] for R⁷/q,[F0] for W/X/Y and [G0] for V.

Preferred intermediates A-12 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-12 have structural aspects selected from [B0] to [B17] for R²/R³, [D0]to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and [F1] for W/X/Y, [G0] and[G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Y altogether. Thesestructural aspects may be permutated with one another as desired incombinations BDEFG, so as to obtain preferred intermediates A-12(aspects E and F can be replaced by combination aspect EF). Eachcombination BDEFG represents and defines individual embodiments orgeneric subsets of intermediates A-12.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-12 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (Ib*).

In a further aspect the invention also relates to syntheticintermediates of formula A-13 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, n, q and r inA-13 correspond to those as given for compound (I), (a), (Ib), (Ic),(Ia*), (Ib*) or (c*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [D0]for n, [E0] for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates A-13 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-13 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [D0] to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and[F1] for W/X/Y, [G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Yaltogether. These structural aspects may be permutated with one anotheras desired in combinations BCDEFG, so as to obtain preferredintermediates A-13 (aspects E and F can be replaced by combinationaspect EF). Each combination BCDEFG represents and defines individualembodiments or generic subsets of intermediates A-13.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-13 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (Ib*).

In a further aspect the invention also relates to syntheticintermediates of formula A-14 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, n, q and r inA-15 correspond to those as given for compound (I), (a), (Ib), (Ic),(Ia*), (Ib*) or (c*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [D0]for n, [E0] for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates A-14 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-14 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [D0] to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and[F1] for W/X/Y, [G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Yaltogether. These structural aspects may be permutated with one anotheras desired in combinations BCDEFG, so as to obtain preferredintermediates A-14 (aspects E and F can be replaced by combinationaspect EF). Each combination BCDEFG represents and defines individualembodiments or generic subsets of intermediates A-14.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-14 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (Ib*).

In a further aspect the invention also relates to syntheticintermediates of formula A-15 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R³, R⁴, R⁷, A, V, W, X, Y, n, q and r inA-15 correspond to those as given for compound (I), (a), (Ib), (Ic),(Ia*), (Ib*) or (c*) above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r, [D0]for n, [E0] for R⁷/q, [F0] for W/X/Y and [G0] for V.

Preferred intermediates A-15 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-15 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r, [D0] to [D3] for n, [E0] to [E2] for R⁷/q, [F0] and[F1] for W/X/Y, [G0] and [G1] for V and [EF0] and [EF1] for R⁷/q/W/X/Yaltogether. These structural aspects may be permutated with one anotheras desired in combinations BCDEFG, so as to obtain preferredintermediates A-15 (aspects E and F can be replaced by combinationaspect EF). Each combination BCDEFG represents and defines individualembodiments or generic subsets of intermediates A-15.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-15 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (b*).

In a further aspect the invention also relates to syntheticintermediates of formula A-17 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R, R⁴, A and r in A-17 correspond to thoseas given for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (c*) above,i.e. [B0] for R²/R³ and [C0] for A/R⁴/r.

Preferred intermediates A-17 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-17 have structural aspects selected from [B0] to [B17] for R²/R³ and[C0] to [C15] for A/R⁴/r. These structural aspects may be permutatedwith one another as desired in combinations BC, so as to obtainpreferred intermediates A-17. Each combination BC represents and definesindividual embodiments or generic subsets of intermediates A-17.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-17 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (b*).

In a further aspect the invention also relates to syntheticintermediates of formula A-18 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R³, R⁴, A and r in A-18 correspond tothose as given for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (c*)above, i.e. [B0] for R²/R³ and [C0] for A/R⁴/r.

Preferred intermediates A-18 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-18 have structural aspects selected from [B0] to [B17] for R²/R³ and[C0] to [C15] for A/R⁴/r. These structural aspects may be permutatedwith one another as desired in combinations BC, so as to obtainpreferred intermediates A-18. Each combination BC represents and definesindividual embodiments or generic subsets of intermediates A-18.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-18 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (Ib*).

In a further aspect the invention also relates to syntheticintermediates of formula A-20 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R³, R⁴, A, n and r in A-20 correspond tothose as given for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (c*)above, i.e. [B0] for R²/R³, [C0] for A/R⁴/r and [D0] for n.

Preferred intermediates A-20 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-20 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r and [D0] to [D3] for n. These structural aspects maybe permutated with one another as desired in combinations BCD, so as toobtain preferred intermediates A-20. Each combination BCD represents anddefines individual embodiments or generic subsets of intermediates A-20.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-20 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (b*).

In a further aspect the invention also relates to syntheticintermediates of formula A-21 and their salts, which can be used as keyintermediates in the synthesis of compounds of formula (Ib) and (Ib*):

The definitions of groups R², R, R⁴, A, n and r in A-21 correspond tothose as given for compound (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (c*)above, i.e. [B0] for R²/R, [C0] for A/R⁴/r and [D0] for n.

Preferred intermediates A-21 are those which lead to preferred compounds(Ib) and (Ib*) according to the invention, i.e. preferred embodiments ofA-21 have structural aspects selected from [B0] to [B17] for R²/R³, [C0]to [C15] for A/R⁴/r and [D0] to [D3] for n. These structural aspects maybe permutated with one another as desired in combinations BCD, so as toobtain preferred intermediates A-21. Each combination BCD represents anddefines individual embodiments or generic subsets of intermediates A-21.

In a further aspect the invention also relates to the use of syntheticintermediates of formula A-21 or their salts (and the variousembodiments and sub-groups as described and/or defined herein) in thesynthesis of compounds (Ib) and (b*).

The present invention further relates to hydrates, solvates, polymorphs,metabolites, derivatives, isomers and prodrugs of a compound of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*).

Compounds of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) whiche.g. bear ester groups are potential prodrugs the ester being cleavedunder physiological conditions.

The present invention further relates to a pharmaceutically acceptablesalt of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or(c*).

The present invention further relates to a co-crystal, preferably apharmaceutically acceptable co-crystal, of a compound of formula (I),(a), (Ib), (Ic), (Ia*), (Ib*) or (c*).

In one aspect compounds (I), (a), (Ib), (Ic), (Ia*), (Ib*) or (c*)according to the invention are in amorphous form.

The present invention further relates to a pharmaceutically acceptablesalt of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or(Ic*) with inorganic or organic acids or bases.

The present invention is directed to compounds of formula (I), (Ia),(Ib), (Ic), (Ia*), (Ib*) or (Ic*) which are useful in the preventionand/or treatment of a disease and/or condition wherein the inhibition ofthe interaction between MDM2 and p53 is of therapeutic benefit,including but not limited to the treatment and/or prevention of cancer.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use as a medicament.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in a method for treatment of the human or animalbody.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in the treatment and/or prevention of a diseaseand/or condition wherein the inhibition of the interaction between MDM2and p53 is of therapeutic benefit.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in the treatment and/or prevention of cancer,infections, inflammations or autoimmune diseases.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in a method for treatment and/or prevention ofcancer, infections, inflammations or autoimmune diseases in the humanand animal body.

In another aspect the invention relates to the use of a compound offormula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or apharmaceutically acceptable salt thereof—for preparing a pharmaceuticalcomposition for the treatment and/or prevention of cancer, infections,inflammations or autoimmune diseases.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in the treatment and/or prevention of cancer.

In another aspect the invention relates to the use of a compound offormula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or apharmaceutically acceptable salt thereof—for preparing a pharmaceuticalcomposition for the treatment and/or prevention of cancer.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in a method for treatment and/or prevention ofcancer in the human or animal body.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in the treatment and/or prevention of acute myeloidleukaemia (AML), prostate cancer or lung cancer, wherein the cancercells have functional p53, preferably wherein the cancer cells are p53wild-type.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in the treatment and/or prevention of acute myeloidleukaemia (AML), prostate cancer or lung cancer, wherein the cancercells preferably have functional p53, more preferably wherein the cancercells are p53 wild-type.

In another aspect the invention relates to the use of a compound offormula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or apharmaceutically acceptable salt thereof—for preparing a pharmaceuticalcomposition for the treatment and/or prevention of acute myeloidleukaemia (AML), prostate cancer or lung cancer, wherein the cancercells have functional p53, preferably wherein the cancer cells are p53wild-type.

In another aspect the invention relates to the use of a compound offormula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or apharmaceutically acceptable salt thereof—for preparing a pharmaceuticalcomposition for the treatment and/or prevention of acute myeloidleukaemia (AML), prostate cancer or lung cancer, wherein the cancercells preferably have functional p53, more preferably wherein the cancercells are p53 wild-type.

In another aspect the invention relates to a method for the treatmentand/or prevention of a disease and/or condition wherein the inhibitionof the interaction between MDM2 and p53 is of therapeutic benefitcomprising administering a therapeutically effective amount of acompound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or apharmaceutically acceptable salt thereof—to a human being.

In another aspect the invention relates to a method for the treatmentand/or prevention of cancer comprising administering a therapeuticallyeffective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Ia*),(Ib*) or (Ic*)—or a pharmaceutically acceptable salt thereof—to a humanbeing.

In another aspect the invention relates to a pharmaceutical compositioncomprising at least one compound of formula (I), (Ia), (Ib), (Ic),(Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptable salt thereof—anda pharmaceutically acceptable carrier.

In another aspect the invention relates to a pharmaceutical preparationcomprising a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or(Ic*)—or a pharmaceutically acceptable salt thereof—and at least oneother cytostatic and/or cytotoxic active substance.

In another aspect the invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptablesalt thereof—for use in the treatment and/or prevention of cancer,infections, inflammations or autoimmune diseases wherein said compoundis administered before, after or together with at least one othercytostatic or cytotoxic active substance.

In another aspect the invention relates to the use of a compound offormula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or apharmaceutically acceptable salt thereof—for preparing a medicament forthe treatment and/or prevention of cancer, infections, inflammations orautoimmune diseases wherein said compound is administered before, afteror together with at least one other cytostatic or cytotoxic activesubstance.

In another aspect the invention relates to a cytostatic or cytotoxicactive substance prepared for being administered before, after ortogether with a compound of formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*)or (Ic*)—or a pharmaceutically acceptable salt thereof—for use in thetreatment and/or prevention of cancer, infections, inflammations orautoimmune diseases.

In another aspect the invention relates to a method for the treatmentand/or prevention of cancer, infections, inflammations or autoimmunediseases comprising administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I), (Ia),(Ib), (Ic), (Ia*), (Ib*) or (Ic*)—or a pharmaceutically acceptable saltthereof—before, after or together with at least one other cytostatic orcytotoxic active substance.

Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to:

The use of the prefix C_(x-y), wherein x and y each represent a naturalnumber (x<y), indicates that the chain or ring structure or combinationof chain and ring structure as a whole, specified and mentioned indirect association, may consist of a maximum of y and a minimum of xcarbon atoms.

The indication of the number of members in groups that contain one ormore heteroatom(s) (e.g. heteroalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocycylalkyl) relates to the total number of atoms ofall the ring members or chain members or the total of all the ring andchain members.

The indication of the number of carbon atoms in groups that consist of acombination of carbon chain and carbon ring structure (e.g.cycloalkylalkyl, arylalkyl) relates to the total number of carbon atomsof all the carbon ring and carbon chain members. Obviously, a ringstructure has at least three members.

In general, for groups comprising two or more subgroups (e.g.heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the lastnamed subgroup is the radical attachment point, for example, thesubstituent aryl-C₁₋₆alkyl means an aryl group which is bound to aC₁₋₆alkyl group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may bepresent in both straight-chain (unbranched) and branched form. If analkyl is substituted, the substitution may take place independently ofone another, by mono- or polysubstitution in each case, on all thehydrogen-carrying carbon atoms.

The term “C₁₋₅alkyl” includes for example H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—,H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—,H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—,H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—,H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃),1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl;—CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu;—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃),1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl(—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃),3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl(—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃),1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl,2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl,3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl,1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, wherein allisomeric forms are included.

The above definition for alkyl also applies if alkyl is a part ofanother (combined) group such as for example C_(x-y)alkylamino orC_(x-y)alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent,unlike alkyl, and requires two binding partners. Formally, the secondvalency is produced by removing a hydrogen atom in an alkyl.Corresponding groups are for example —CH₃ and —CH₂—, —CH₂CH₃ and—CH₂CH₂— or >CHCH₃ etc.

The term “C₁₋₄alkylene” includes for example —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CH(CH(CH₃))₂)—and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc.without any further definition are meant all the conceivable isomericforms with the corresponding number of carbon atoms, i.e. propyleneincludes 1-methylethylene and butylene includes 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part ofanother (combined) group such as for example in HO—C_(x-y)alkyleneaminoor H₂N—C_(x-y)alkyleneoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C═C double bondand a carbon atom can only be part of one C═C double bond. If in analkyl as hereinbefore defined having at least two carbon atoms, twohydrogen atoms on adjacent carbon atoms are formally removed and thefree valencies are saturated to form a second bond, the correspondingalkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl(prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl,2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl,1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl,3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl,2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl,hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl,2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyletc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenyl includes prop-1-enyl and prop-2-enyl, butenyl includesbut-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl,1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part ofanother (combined) group such as for example in C_(x-y)alkenylamino orC_(x-y)alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C═Cdouble bond and a carbon atom can only be part of one C═C double bond.If in an alkylene as hereinbefore defined having at least two carbonatoms, two hydrogen atoms at adjacent carbon atoms are formally removedand the free valencies are saturated to form a second bond, thecorresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene,butenylene, 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene,2,2-dimethylpropenylene, 1,2-dimethylpropenylene,1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenylene includes 1-methylethenylene and butenylene includes1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is apart of another (combined) group as for example inHO—C_(x-y)alkenyleneamino or H₂N—C_(x-y)alkenyleneoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C triplebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms in each case at adjacent carbon atoms areformally removed and the free valencies are saturated to form twofurther bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl,pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl,hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl etc. without any further definition are meantall the conceivable isomeric forms with the corresponding number ofcarbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl,butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl,1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also atleast one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part ofanother (combined) group, as for example in C_(x-y)alkynylamino orC_(x-y)alkynyloxy.

Unlike alkylene, alkynylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Ctriple bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms in each case at adjacent carbonatoms are formally removed and the free valencies are saturated to formtwo further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propynylene includes 1-methylethynylene and butynylene includes1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is partof another (combined) group, as for example in HO—C_(x-y)alkynyleneaminoor H₂N—C_(x-y)alkynyleneoxy.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previouslydefined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atomsof the hydrocarbon chain independently of one another by halogen atoms,which may be identical or different. If a haloalkyl (haloalkenyl,haloalkynyl) is to be further substituted, the substitutions may takeplace independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃,—CF═CF₂, —CCl═CH₂, —CBr═CH₂, —C═C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃ etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) arealso derived the terms haloalkylene (haloalkenylene, haloalkynylene).Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl(haloalkenyl, haloalkynyl), is bivalent and requires two bindingpartners. Formally, the second valency is formed by removing a hydrogenatom from a haloalkyl (haloalkenyl, haloalkynyl).

Corresponding groups are for example —CH₂F and —CHF—, —CHFCH₂F and—CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen-containinggroups are part of another (combined) group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems aresaturated. In bicyclic hydrocarbon rings two rings are joined togetherso that they have at least two carbon atoms together. Inspiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two ringstogether.

If a cycloalkyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl(octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl),bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl),bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is partof another (combined) group as for example in C_(x-y)cycloalkylamino,C_(x-y)cycloalkyloxy or C_(x-y)cycloalkylalkyl.

If the free valency of a cycloalkyl is saturated, then an alicyclicgroup is obtained.

The term cycloalkylene can thus be derived from the previously definedcycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requirestwo binding partners. Formally, the second valency is obtained byremoving a hydrogen atom from a cycloalkyl. Corresponding groups are forexample:

The above definition for cycloalkylene also applies if cycloalkylene ispart of another (combined) group as for example inHO—C_(x-y)cycloalkyleneamino or H₂N—C_(x-y)cycloalkyleneoxy.

Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbonrings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However,the systems are unsaturated, i.e. there is at least one C═C double bondbut no aromatic system. If in a cycloalkyl as hereinbefore defined twohydrogen atoms at adjacent cyclic carbon atoms are formally removed andthe free valencies are saturated to form a second bond, thecorresponding cycloalkenyl is obtained.

If a cycloalkenyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkenylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl,cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl,cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl,cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl,cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl,cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl,bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl),bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl etc.

The above definition for cycloalkenyl also applies when cycloalkenyl ispart of another (combined) group as for example inC_(x-y)cycloalkenylamino, C_(x-y)cycloalkenyloxy orC_(x-y)cycloalkenylalkyl.

If the free valency of a cycloalkenyl is saturated, then an unsaturatedalicyclic group is obtained.

The term cycloalkenylene can thus be derived from the previously definedcycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent andrequires two binding partners.

Formally, the second valency is obtained by removing a hydrogen atomfrom a cycloalkenyl. Corresponding groups are for example:

The above definition for cycloalkenylene also applies if cycloalkenyleneis part of another (combined) group as for example inHO—C_(x-y)cycloalkenyleneamino or H₂N—C_(x-y)cycloalkenyleneoxy.

Aryl denotes mono-, bi- or tricyclic carbocycles with at least onearomatic carbocycle. Preferably, it denotes a monocyclic group with sixcarbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms(two six-membered rings or one six-membered ring with a five-memberedring), wherein the second ring may also be aromatic or, however, mayalso be partially saturated.

If an aryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Aryl itself maybe linked as a substituent to the molecule via every suitable positionof the ring system.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl),indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl(1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl(1,2-dihydronaphthyl), fluorenyl etc.

The above definition of aryl also applies if aryl is part of another(combined) group as for example in arylamino, aryloxy or arylalkyl.

If the free valency of an aryl is saturated, then an aromatic group isobtained.

The term arylene can also be derived from the previously defined aryl.Arylene, unlike aryl, is bivalent and requires two binding partners.Formally, the second valency is formed by removing a hydrogen atom froman aryl. Corresponding groups are for example: phenyl and or or (o, m,p-phenylene),

The above definition for arylene also applies if arylene is part ofanother (combined) group as for example in HO-aryleneamino orH₂N-aryleneoxy.

Heterocyclyl denotes ring systems, which are derived from the previouslydefined cycloalkyl, cycloalkenyl and aryl by replacing one or more ofthe groups —CH₂— independently of one another in the hydrocarbon ringsby the groups —O—, —S— or —NH— or by replacing one or more of the groups═CH— by the group ═N—, wherein a total of not more than five heteroatomsmay be present, at least one carbon atom must be present between twooxygen atoms and between two sulphur atoms or between an oxygen and asulphur atom and the ring as a whole must have chemical stability.Heteroatoms may optionally be present in all the possible oxidationstages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide). In aheterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is partof an aromatic system.

A direct result of the derivation from cycloalkyl, cycloalkenyl and arylis that heterocyclyl is made up of the subgroups monocyclic heterorings,bicyclic heterorings, tricyclic heterorings and spiro-heterorings, whichmay be present in saturated or unsaturated form.

By unsaturated is meant that there is at least one double bond in thering system in question, but no heteroaromatic system is formed. Inbicyclic heterorings two rings are linked together so that they have atleast two (hetero)atoms in common. In spiro-heterorings one carbon atom(spiroatom) belongs to two rings together.

If a heterocyclyl is substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heterocyclyl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl,1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl,tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl,1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl,8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl,2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl,2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl,1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl,2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl,3,9-diaza-spiro[5.5]undecyl, 2.8-diaza-spiro[4,5]decyl etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferably, heterocyclyls are 4 to 8 membered, monocyclic and have oneor two heteroatoms independently selected from oxygen, nitrogen andsulfur Preferred heterocyclyls are: piperazinyl, piperidinyl,morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl,tetrahydrofuranyl.

The above definition of heterocyclyl also applies if heterocyclyl ispart of another (combined) group as for example in heterocyclylamino,heterocyclyloxy or heterocyclylalkyl.

If the free valency of a heterocyclyl is saturated, then a heterocyclicgroup is obtained.

The term heterocyclylene is also derived from the previously definedheterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heterocyclyl. Corresponding groupsare for example:

The above definition of heterocyclylene also applies if heterocyclyleneis part of another (combined) group as for example inHO-heterocyclyleneamino or H₂N-heterocyclyleneoxy.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic ringswith at least one heteroaromatic ring, which compared with thecorresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of oneor more carbon atoms, one or more identical or different heteroatoms,selected independently of one another from among nitrogen, sulphur andoxygen, wherein the resulting group must be chemically stable. Theprerequisite for the presence of heteroaryl is a heteroatom and aheteroaromatic system.

If a heteroaryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heteroaryl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system, both carbon and nitrogen.

Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide,thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl,benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl,indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl,benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl,benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide,indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide,quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 memberedbicyclic, each with 1 to 4 heteroatoms independently selected fromoxygen, nitrogen and sulfur.

The above definition of heteroaryl also applies if heteroaryl is part ofanother (combined) group as for example in heteroarylamino,heteroaryloxy or heteroarylalkyl.

If the free valency of a heteroaryl is saturated, a heteroaromatic groupis obtained.

The term heteroarylene is also derived from the previously definedheteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requirestwo binding partners. Formally, the second valency is obtained byremoving a hydrogen atom from a heteroaryl.

Corresponding groups are for example:

The above definition of heteroarylene also applies if heteroarylene ispart of another (combined) group as for example in HO-heteroaryleneaminoor H₂N-heteroaryleneoxy.

By substituted is meant that a hydrogen atom which is bound directly tothe atom under consideration, is replaced by another atom or anothergroup of atoms (substituent). Depending on the starting conditions(number of hydrogen atoms) mono- or polysubstitution may take place onone atom. Substitution with a particular substituent is only possible ifthe permitted valencies of the substituent and of the atom that is to besubstituted correspond to one another and the substitution leads to astable compound (i.e. to a compound which is not convertedspontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂or the like, may only be substituents on carbon atoms, wherein thebivalent substituent ═O may also be a substituent on sulphur. Generally,substitution may be carried out by a bivalent substituent only at ringsystems and requires replacement of two geminal hydrogen atoms, i.e.hydrogen atoms that are bound to the same carbon atom that is saturatedprior to the substitution. Substitution by a bivalent substituent istherefore only possible at the group —CH₂— or sulphur atoms (═O only) ofa ring system.

Stereochemistry/solvates/hydrates: Unless specifically indicated,throughout the specification and appended claims, a given chemicalformula or name shall encompass tautomers and all stereo, optical andgeometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.)and racemates thereof as well as mixtures in different proportions ofthe separate enantiomers, mixtures of diastereomers, or mixtures of anyof the foregoing forms where such isomers and enantiomers exist, as wellas salts, including pharmaceutically acceptable salts thereof andsolvates thereof such as for instance hydrates including solvates of thefree compounds or solvates of a salt of the compound.

Salts: The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, and commensurate with a reasonable benefit/risk ratio.

As used herein “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

For example, such salts include salts from ammonia, L-arginine, betaine,benethamine, benzathine, calcium hydroxide, choline, deanol,diethanolamine (2,2′-iminobis(ethanol)), diethylamine,2-(diethylamino)-ethanol, 2-(dimethylamino)-ethanol, 2-aminoethanol,ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine(L-lysine), proline (L-proline), magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine,1-(2-hydroxyethyl)-pyrrolidone, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol), tromethamine, zinc hydroxide, aceticacid, 2,2-dichloro acetic acid, adipic acid, alginic acid, ascorbic acid(L), L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid (capric acid), dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonicacid, ethylenediaminetetraacetic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid,D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid,glycerophosphoric acid, glycine, glycolic acid, hexanoic acid (caproicacid), hippuric acid, hydrobromic acid, hydrochloric acid, isobutyricacid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid,(−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid(caprylic acid), oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid (embonic acid), phosphoric acid, propionic acid,(−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid.

The salts include acetates, ascorbates, benzenesulfonates, benzoates,besylates, bicarbonates, bitartrates, bromides/hydrobromides,Ca-edetates/edetates, camsylates, carbonates, camphorsulfonate,chlorides/hydrochlorides, chlorotheophyllinate, citrates, edisylates,ethane disulfonates, estolates esylates, fumarates, gluceptates,gluconates, glucuronate, glutamates, glycolates, glycollylarsnilates,hexylresorcinates, hippurate, hydrabamines, hydroxymaleates,hydroxynaphthoates, iodides, isethionates, isothionates, lactates,lactobionates, laurylsulfates, malates, maleates, mandelates,methanesulfonates, mesylates, methylbromides, methylnitrates,methylsulfates, mucates, naphthoate, napsylates, nitrates,octadecanoates, oleates, oxalates, pamoates, pantothenates,phenylacetates, phosphates/diphosphates, polygalacturonates,propionates, salicylates, stearates subacetates, succinates, sulfamides,sulfates, sulfosalicylates, tannates, tartrates, teoclates,toluenesulfonates, triethiodides, trifluoroacetates, ammonium,benzathines, chloroprocaines, cholines, diethanolamines,ethylenediamines, meglumines and procaines.

Further pharmaceutically acceptable salts can be formed with cationsfrom metals like aluminium, calcium, lithium, magnesium, potassium,sodium, zinc and the like (also see Pharmaceutical salts, Berge, S. M.et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base form of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts), also comprise a part of the invention.

The present invention also includes the co-crystals of any compoundaccording to the invention, i.e. those crystalline forms composed of atleast two components (one being the compound according to the invention,the other being co-crystal formers) forming a unique crystallinestructure without, in contrast to the crystalline salts, proton transferfrom one component to the other. Potential co-crystal formers are acidsand bases as listed above for salts/salt formers.

In a representation such as for example

the letter A has the function of a ring designation in order to make iteasier, for example, to indicate the attachment of the ring in questionto other rings.

For bivalent groups in which it is crucial to determine which adjacentgroups they bind and with which valency, the corresponding bindingpartners are indicated in brackets where necessary for clarificationpurposes, as in the following representations:

(R²)—C(O)NH— or (R²)—NHC(O)—;

Groups or substituents are frequently selected from among a number ofalternative groups/substituents with a corresponding group designation(e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define acompound according to the invention in different parts of the molecule,it is pointed out that the various uses are to be regarded as totallyindependent of one another.

By a therapeutically effective amount for the purposes of this inventionis meant a quantity of substance that is capable of obviating symptomsof illness or of preventing or alleviating these symptoms, or whichprolong the survival of a treated patient.

The term “about” when used to specify a temperature or a temperaturerange usually means the temperature given ±5° C., when used to specify apressure or a pressure range the pressure given ±0.5 bar. In all othercases “about” includes the range ±5% around the specific value given.

List of abbreviations Ac acetyl acac acetylacetonate AcCN acetonitrileaq. aquatic, aqueous ATP adenosine triphosphate Bn benzyl Boctert-butyloxycarbonyl Bu butyl c concentration d day(s) dbadibenzylideneacetone TLC thin layer chromatography DABCO1,4-diazabicyclo[2.2.2]octan Davephos 2-dimethylamino-2′-dicyclohexylaminophosphinobiphenyl DBA dibenzylideneacetone DCMdichloromethane DEA diethylamine DEAD diethyl azodicarboxylate DIPAN,N-diisopropylamine DIPEA N-ethyl-N,N-diisopropylamine (Hünig's base)DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethylsulphoxide DPPAdiphenylphosphorylazide dppf 1.1′-bis(diphenylphosphino)ferrocene EDTAethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acid eqequivalent(s) ESI electron spray ionization Et ethyl Et₂O diethyl etherEtOAc ethyl acetate EtOH ethanol h hour HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uroniumhexafluorophosphate HPLC high performance liquid chromatography IBX2-iodoxy benzoic acid i iso conc. concentrated LC liquid chromatographyLiHMDS lithium bis(trimethylsilyl)amide sln. solution MCH methylcyclohexane Me methyl MeOH methanol min minutes MPLC medium pressureliquid chromatography MS mass spectrometry MTBE methyl tert-butyl etherNBS N-bromo-succinimide NIS N-iodo-succinimide NMM N-methylmorpholineNMP N-methylpyrrolidone NP normal phase n.a. not available PBSphosphate-buffered saline Ph phenyl Pr propyl Py pyridine rac racemicred. reduction Rf (R_(f)) retention factor RP reversed phase rt ambienttemperature SFC supercritical fluid chromatography S_(N) nucleophilicsubstitution TBAF tetrabutylammonium fluoride TBDMStert-butyldimethylsilyl TBME tert-butylmethylether TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uronium tetrafluoroboratetBu tert-butyl TEA triethylamine temp. temperature tert tertiary Tftriflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilylt_(Ret.) retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethaneTsOH p-toluenesulphonic acid UV ultraviolet

Features and advantages of the present invention will become apparentfrom the following detailed examples which illustrate the principles ofthe invention by way of example without restricting its scope:

Preparation of the Compounds According to the Invention

General

Unless stated otherwise, all the reactions are carried out incommercially obtainable apparatus using methods that are commonly usedin chemical laboratories. Starting materials that are sensitive to airand/or moisture are stored under protective gas and correspondingreactions and manipulations therewith are carried out under protectivegas (nitrogen or argon).

The compounds according to the invention are named in accordance withCAS rules using the software Autonom (Beilstein). If a compound is to berepresented both by a structural formula and by its nomenclature, in theevent of a conflict the structural formula is decisive.

Microwave reactions are carried out in an initiator/reactor made byBiotage or in an Explorer made by CEM or in Synthos 3000 or Monowave3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL),preferably with stirring.

Chromatography

The thin layer chromatography is carried out on ready-made silica gel 60TLC plates on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (RP HPLC) of the examplecompounds according to the invention is carried out on Agilent or Gilsonsystems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10μm, 50×150 mm or SunFire™ Prep C18 OBD™ 5 μm, 30×50 mm or XBridge™ PrepC18, OBD™ 10 μm, 50×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×150 mm orXBridge™ Prep C18, OBD™ 5 μm, 30×50 mm) and YMC (names: Actus-TriartPrep C18, 5 μm, 30×50 mm).

Different gradients of H₂O/acetonitrile are used to elute the compounds,while for Agilent systems 5% acidic modifier (20 mL HCOOH to 1 LH₂O/acetonitrile (1/1)) is added to the water (acidic conditions). ForGilson systems the water is added 0.1% HCOOH.

For the chromatography under basic conditions for Agilent systemsH₂O/acetonitrile gradients are used as well, while the water is madealkaline by addition of 5% basic modifier (50 g NH₄HCO₃+50 mL NH₃ (25%in H₂O) to 1 L with H₂O). For Gilson systems the water is made alkalineas follows: 5 mL NH₄HCO₃ solution (158 g in 1 L H₂O) and 2 mL NH₃ (28%in H₂O) are replenished to 1 L with H₂O.

The supercritical fluid chromatography (SFC) of the intermediates andexample compounds according to the invention is carried out on a JASCOSFC-system with the following columns: Chiralcel OJ (250×20 mm, 5 μm),Chiralpak AD (250×20 mm, 5 μm), Chiralpak AS (250×20 mm, 5 μm),Chiralpak IC (250×20 mm, 5 μm), Chiralpak IA (250×20 mm, 5 μm),Chiralcel OJ (250×20 mm, 5 μm), Chiralcel OD (250×20 mm, 5 μm),Phenomenex Lux C2 (250×20 mm, 5 μm).

The analytical HPLC (reaction control) of intermediate and finalcompounds is carried out using columns made by Waters (names: XBridge™C18, 2.5 μm, 2.1×20 mm or XBridge™ C18, 2.5 μm, 2.1×30 mm or Aquity UPLCBEH C18, 1.7 μm, 2.1×50 mm) and YMC (names: Triart C18, 3.0 μm, 2.0×30mm) and Phenomenex (names: Luna C18, 5.0 μm, 2.0×30 mm). The analyticalequipment is also equipped with a mass detector in each case.

HPLC-Mass Spectroscopy/UV-Spectrometry

The retention times/MS-ESI+ for characterizing the example compoundsaccording to the invention are produced using an HPLC-MS apparatus (highperformance liquid chromatography with mass detector). Compounds thatelute at the injection peak are given the retention time t_(Ret).=0.00.

HPLC-Methods:

Method A HPLC Agilent 1100 Series MS Agilent LC/MSD SL column Waters,Xbridge ™ C18, 2.5 μn, 2.1 × 20 mm, Part.No. 186003201 solvent A: 20 mMNH₄HCO₃/NH₃ pH 9 B: acetonitrile (HPLC grade) detection MS: positive andnegative mass range: 120-900 m/z fragmentor: 120 gain EMV: 1 threshold:150 stepsize: 0.2 UV: 315 nm bandwidth: 170 nm reference: off range:230-400 nm range step: 1.00 nm peakwidth: <0.01 min slit: 1 nm injection5 μL flow 1.00 mL/min column temperature 60° C. gradient 0.00 min 10% B0.00-1.50 min 10% → 95% B 1.50-2.00 min 95% B 2.00-2.10 min 95% → 10% BMethod B HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MScolumn Waters, Xbridge ™ C18, 2.5 μm, 2.1 × 30 mm solvent A: 20 mMNH₄HCO₃/NH₃ in water; pH 9.3 B: acetonitrile (HPLC grade) detection MS:polarity: positive ionizator: MM-ES + APCI mass range: 150-750 m/zfragmentor values: mass fragmentor 150  70 750 110 gain EMV: 1.00threshold: 150 stepsize: 0.2 UV: 254 nm: reference off 214 nm: referenceoff range: 190-400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth:0.0025 min (0.05 s) slit: 4 nm injection 0.5 μL flow 1.400 mL/min columntemperature 45° C. gradient 0.00-1.00 min 15% -> 95% B 1.00-1.30 min 95%B Method C HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MScolumn YMC, Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water +0.1% HCOOH B: acetonitrile + 0.1% HCOOH (HPLC grade) detection MS:polarity: positive mass range: 150-750 m/z fragmentor values: massfragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.20UV: 254 nm: reference off 214 nm: reference off range: 190-400 nm rangestep: 4.00 nm threshold: 1.00 mAU peakwidth: 0.005 min (0.1 s) slit: 4nm injection 0.5 μL flow 1.400 mL/min column temperature 45° C. gradient0.0-1.00 min 15% → 100% B 1.00-1.13 min 100% B Method D HPLC Agilent1200 Series MS Agilent 6130 Quadropole LC/MS column Waters, Xbridge ™C18, 2.5 μm, 2.1 × 30 mm solvent A: 20 mM NH₄HCO₃/NH₃ in water; pH 9.3B: acetonitrile (HPLC grade) detection MS: polarity: positive + negativeionization: MM-ES mass range: 150-750 m/z fragmentor values: massfragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.2UV: 254 nm: reference off 214 nm: reference off range: 190-400 nm rangestep: 2.00 nm threshold: 1.00 mAU peakwidth: 0.0025 min (0.05 s) slit: 4nm injection 0.5 μL flow 1.400 mL/min column temperature 45° C. gradient0.00 -1.00 min 15% → 95% B 1.00-1.30 min 95% B Method E HPLC Agilent1200 Series: MS Agilent 6130 Quadropole LC/MS column Waters, Xbridge ™C18, 2.5 μm, 2.1 × 30 mm Column XP; Part.No. 186006028 solvent A: 20 mMNH₄HCO₃/NH₃ in water; pH 9.3 B: acetonitrile (HPLC grade) detection MS:polarity: positive + negative ionizator: API-ES mass range: 150-750 m/zfragmentor values: mass fragmentor 150  70 750 110 gain EMV: 1.00threshold: 150 stepsize: 0.2 UV: 254 nm: reference off 214 nm: referenceoff range: 190-400 nm range step: 2.00 nm threshold: 1.00 mAU peakwidth:0.0025 min (0.05 s) slit: 4 nm injection 0.5 μL flow 1.400 mL/min columntemperature 45° C. gradient 0.00-1.00 min 15% → 95% B 1.00-1.30 min 95%B Method F HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MScolumn YMC, Triart C18, 3.0 μm, 2.0 ×30 mm, 12 nm solvent A: water +0.1% HCOOH B: acetonitrile + 0.1% HCOOH (HPLC grade) detection MS:polarity: positive + negative mass range: 150-750 m/z fragmentor values:mass fragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150 stepsize:0.20 UV: 254 nm: reference off 214 nm: reference off range: 190-400 nmrange step: 4.00 nm threshold: 1.00 mAU peakwidth: 0.0063 min (0.13 s)slit: 4 nm injection 0.5 μL flow 1.400 mL/min column temperature 45° C.gradient 0.00-1.00 min 15% → 100% B 1.00-1.13 min 100% B Method G HPLCAgilent 1200 Series MS Agilent 6130 Quadropole LC/MS column YMC, TriartC18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water +0.1% HCOOH B:acetonitrile + 0.1% HCOOH (HPLC grade) detection MS: polarity:positive + negative mass range: 150-750 m/z fragmentor values: MassFragmentor 150  70 750 110 gain EMV: 1.00 threshold: 150 stepsize: 0.20UV: 254 nm: reference off 230 nm: reference off 214 nm: reference offrange: 190-400 nm range step: 4.00 nm threshold: 1.00 mAU peakwidth:0.005 min (0.1 s) slit: 4 nm injection 0.5 μL flow 1.400 mL/min columntemperature 45° C. gradient 0.00-1.00 min 15% → 100% B 1.00-1.13 min100% B Method H HPLC Agilent 1200 Series MS Agilent 6130 QuadropoleLC/MS column YMC, Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A:water + 0.1% HCOOH B: acetonitrile + 0.1% HCOOH (HPLC grade) detectionMS: polarity: positive + negative mass range: 200-800 m/z fragmentor :70 gain: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: reference off230 nm: reference off range: 190-400 nm range step: 2.00 nmpeakwidth: >0.01 min (0.2 s) slit: 4 nm injection 1.0 μL flow 1.000mL/min column temperature 45° C gradient 0.00-0.10 min 5% B 0.10-1.85min 5% B → 95.0% B 1.85-1.90 min 95%B 1.95-1.92 min 95% B → 5.0% BMethod I HPLC Agilent 1200 Series MS Agilent 6130 Quadropole LC/MScolumn YMC, Triart C18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water +0.1% HCOOH B: acetonitrile + 0.1% HCOOH (HPLC grade) detection MS:polarity: positive + negative mass range: 200-800 m/z fragmentor: 70gain: 1.00 threshold: 150 stepsize: 0.20 UV: 254 nm: reference off 230nm: reference off range: 190-400 nm range step: 2.00 nm peakwidth: >0.01min (0.2 s) slit: 4 nm injection 1.0 μL flow 1.000 mL/min columntemperature . 45° C gradient 0.00-0.10 min 15% B 0.10-1.55 min 15% B →95.0% B 1.55-1.90 min 95% B 1.95-1.92 min 95% B → 15.0% B Method J HPLCAgilent 1260 Series MS Agilent 6130 Quadropole LC/MS column YMC, TriartC18, 3.0 μm, 2.0 × 30 mm, 12 nm solvent A: water + 0.1% HCOOH B:acetonitrile (HPLC grade) detection MS: polarity: positive + negativemass range: 100-800 m/z fragmentor: 70 gain: 1.00 threshold: 100stepsize: 0.15 UV: 254 nm: reference off 230 nm: reference off range:190-400 nm range step: 4.00 nm peakwidth: >0.013 min (0.25 s) slit: 4 nminjection 0.5 μL flow 1.400 mL/min column temperature 45° C. gradient0.00-1.00 min 5% → 100% B 1.00-1.37 min 100% B 1.37-1.40 min 100% → 5% BMethod K HPLC Agilent 1260 Series MS Agilent 6130 Quadropole LC/MScolumn Waters, Xbridge ™ C18, 2.5 μm, 2.1 × 30 mm solvent A: 5 mMNH4HCO3/19 mM NH₃ in water B: acetonitrile (HPLC grade) detection MS:polarity: positive + negative mass range: 100-800 m/z fragmentor: 70gain: 1.00 threshold: 100 stepsize: 0.15 UV: 254 nm: reference off 230nm: reference off range: 190-400 nm range step: 4.00 nmpeakwidth: >0.013 min (0.25 s) slit: 4 nm injection 0.5 μL flow 1.400mL/min column temperature 45° C. gradient 0.00-0.01 min 5% B 0.01-1.00min 5% → 100% B 1.00-1.37 min 100% B 1.37-1.40 min 100% → 5% B Method LHPLC/MS Waters UPLC-micromass Triple quad column Aquity UPLC BEH C18,1.7 μM, 2.1 × 50 mm solvent A: water + 0.1% HCOOH B: acetonitrile (HPLCgrade) + 0.1% HCOOH detection MS: ES/APCI positive and negative modemass range: 100-1000 m/z capillary voltage: 3500 V cone voltage: 30-50 Vdisolvation gas: 600 L/h disolvation temp: 300° C. UV: bandwidth: 190 nmrange: 210-400 nm resolution: 1.20 nm sample rate: 5 injection 0.5 μLflow 0.400 mL/min column temperature 40° C. gradient 0.00-1.80 min 0% B1.80-3.80 min 0% → 75% B 3.80-4.50 min 75% → 95% B 4.50-6.00 min 95% B6.00-6.01 min 95% → 0% B Method M HPLC/MS Agilent 1200, 6120MS columnLuna C18(2) 5 μm, 30 × 2.0 mm solvent A: water + 0.037% TFA B:acetonitrile + 0.018% TFA detection MS: positive and negative mode massrange: 100-1000 m/z fragmentor: 70 gain EMV: 1 threshold: 150 stepsize:0.1 UV: 220/254 nm bandwidth: 200 nm reference: off range: 200-400 nmrange step: 0.4 nm Peakwidth: >0.05 min Slit: 4 nm injection 0.5 μL flow1.0 mL/min column temperature 50° C. gradient 0.00-0.30 min 0% B0.30-1.40 min 0% → 60% B 1.40-1.55 min 60% B 1.55-1.56 min 60% → 0% B1.56-2.00 min 0% B

The compounds according to the invention are prepared by the methods ofsynthesis described hereinafter in which the substituents of the generalformulae have the meanings given hereinbefore. These methods areintended as an illustration of the invention without restricting itssubject matter and the scope of the compounds claimed to these examples.Where the preparation of starting compounds is not described, they arecommercially obtainable or may be prepared analogously to known priorart compounds or methods described herein. Substances described in theliterature are prepared according to the published methods of synthesis.

Compounds (Ia) General Reaction Scheme and Summary of the SynthesisRoute

Novel compounds of structure (Ia) can be prepared stepwise starting witha synthesis route depicted in scheme 1 from isatin derivatives S-1 via adecarboxylative 1,3 dipolar cycloaddition with an amino acid B-1 (methodA) or B-5 (method D) and a nitro ethene B-2 to build up spiro systemsB-3 and B-6 as a racemic mixture potentially along with other regio-and/or diastereoisomers of B-3 and B-6. The enantiomers of B-3 and B-6can be separated at this stage by chiral SFC or alternatively theracemic mixture can be separated at any later stage of the synthesis.Also all other means known for separation of enantiomers can be appliedhere or after any later synthetic step herein described, e.g.crystallisation, chiral resolution, chiral HPLC etc. (see alsoEnantiomers, racemates, and resolutions, Jean Jacques, André Collet,Samuel H Wilen John Wiley and Sons, N Y, 1981).

B-3 and B-6 can be reacted with aldehydes or ketones in a reductiveamination reaction to give B-4 (method B) and B-7 (method E).Alternatively, an alkylation, addition, acylation or sulfonylationreaction can be performed with B-3 and B-6 to obtain intermediates B-4and B-7.

Intermediate B-4 can be reduced with DIBAL or another reducing reagentand will then also yield intermediates B-7 (method C).

The hydoxy group of intermediate B-7 is oxidized, e.g. with DESS-MARTINperiodinan, IBX or an alternative oxidizing reagent, to thecorresponding carbonyl compound B-8 (method F, scheme 2) which can befurther reacted with nucleophiles, especially organometallic reagentslike GRIGNARD or organo-zinc reagents (obtainable from B-9 via ametal-halogen exchange reaction) to intermediate B-10 as a mixture oftwo diastereomers (method G).

The diastereoisomers of intermediates B-10 are not separated and used asmixtures for further reactions.

Intermediates B-10 can be oxidized to the ketone intermediates B-11 byusing DESS-MARTIN periodinan, IBX or other oxidation methods (method H).

Reduction of both nitro groups of intermediates B-11 and subsequentreductive cyclization is triggered by treatment of intermediates B-11with hydrogen under RANEY-Ni catalysis, or with alternative reducingagents, and gives intermediates B-12 as a mixture of twodiastereoisomers (method I). The diastereomers of intermediates B-12 arenot separated and used as the mixture for further reactions.

An oxidative cyclization of intermediates B-12 by treatment with OXONE©(potassium peroxymonosulfate) in a mixture of water and DCM, or bytreatment with alternative oxidizing agents gives compounds (Ia)according to the invention (method J). If overoxidation occurs whentreated with OXONE© a subsequent reduction of the crude mixturecontaining overoxidation product B-13 with bis(pinacolato)diborone orother reducing can be performed to yield compounds (Ia).

Compounds (Ia) which are initially obtained from B-12 or B-13 can bederivatized in optional derivatization steps not explicitly depicted inthe schemes in all residues, especially in R⁴, if they carry functionalgroups, that can be further modified such as e.g. halogen atoms, aminoand hydroxy groups (including cyclic amines), carboxylic acid or esterfunctions, nitrils etc. to further compounds (Ia) by well-establishedorganic chemical transformations such as metal-catalyzed cross couplingreactions, acylation, amidation, addition, reduction or (reductive)alkylation or cleavage of protecting groups. These additional steps arenot depicted in the general schemes. Likewise, it is also possible toinclude these additional steps in the synthetic routes depicted in thegeneral schemes, i.e. to carry out derivatization reactions withintermediate compounds. In addition, it may also be possible thatbuilding blocks bearing protecting groups are used, i.e. further stepsfor deprotection are necessary.

Alternatively, compounds (Ia) can also be prepared with the followingreaction sequence:

Starting from anilines or amino heteroaryls B-14 the amino function canbe acetylated with acetic anhydride or other standard acetylationmethods to give intermediates B-15. Intermediates B-15 are brominatedwith NBS, TsOH and Pd(OAc)₂ to yield bromo intermediates B-16.SONOGASHIRA coupling with Boc-prop-2-ynyl-amine under Pd and Cucatalysis gives intermediates B-17 which can by hydratized in acidicconditions under Pd(OAc)₂ catalysis followed by global deprotectionunder acidic conditions (HCl) to yield amines B-18. Modifications ofintermediates thus obtained, e.g. esterification of free carboxyl groups(if one of R⁴=COOH) with SOCl₂ and MeOH or a alternative esterificationmethod, gives additional intermediates B-18. Imine formation ofintermediates B-18 with isatins S-1 gives imine intermediates B-19 whichcan then react in a 1,3 dipolar cycloaddition with nitro ethenes B-2 toyield racemic intermediates B-20 along with other regio- andstereoisomers. The enantiomers of B-20 can be separated at this stage bychiral SFC or alternatively the racemic mixture can be separated at anylater stage of the synthesis, e.g. when intermediate B-22 is reached.Also all other means known for separation of enantiomers can be appliedhere or after any later synthetic step herein described, e.g.crystallisation, chiral resolution, chiral HPLC etc. (see alsoEnantiomers, racemates, and resolutions, Jean Jacques, André Collet,Samuel H Wilen John Wiley and Sons, N Y, 1981). Reduction andcyclisation of intermediate B-20 with H₂ under Pt/C catalysis givesintermediates B-21 which can be reduced subsequently by addition ofVO(acac)₂ to the reaction mixture and continued stirring under H₂pressure to yield intermediates B-22. An oxidative cyclization ofintermediates B-22 with Na₂WO₄ dihydrate and H₂O₂, or by treatment withalternative oxidizing agents gives intermediates B-23 that can beconverted to compounds (Ia) by reactions with aldehydes or ketones in areductive amination reaction. Alternatively, an alkylation, addition,acylation or sulfonylation reaction can be performed with B-23 to obtainadditional compounds (Ia).

Compounds (Ia) have been tested for their activity to affect MDM2-p53interaction in their racemic form or alternatively as the enantiopureform (in particular (Ia*)). Each of the two enantiomers of a racemicmixture may have activity against MDM2 although with a different bindingmode. Enantiopure compounds are marked with the label “Chiral”.Compounds listed in any table below that are labeled “Chiral” (bothintermediates as well as compounds (Ib) according to the invention) canbe separated by chiral SFC chromatography from their enantiomer or aresynthesized from enantiopure starting material which is separated bychiral SFC.

EXAMPLE

Structure A defines the racemic mixture of compounds with structure Band C, i.e. structure A encompasses two structures (compounds B and C),whereas structures B and C, respectively, are enantiopure and onlydefine one specific compound. Thus, formulae (Ia) and (Ia*)

with a set of specific definitions for groups R¹ to R⁴, R⁷, V, W, X, Y,n, r and q represent the racemic mixture of two enantiomers (→(Ia);structure A above is one specific example of such a racemic mixture) ora single enantiomer (→(Ia*); structure B above is one specificenantiomer), unless there are additional stereocenters present in one ormore of the substituents. The same definition applies to syntheticintermediates.

Synthesis of Intermediates B-6 Experimental Procedure for the Synthesisof B-6a (Method D)

6-Chloroisatin S-1a (31.5 g, 174 mmol),1-(3-chloro-2-fluoro-phenyl)-2-nitroethene B-2a (35 g, 174 mmol) andL-homoserine B-5a (20.7 g, 174 mmol) are refluxed in MeOH for 4 h. Thereaction mixture is concentrated in vacuo and purified bycrystallization or chromatography if necessary.

The following intermediates B-6 (table 1) are available in an analogousmanner starting from different annulated 1H-pyrrole-2,3-diones S-1,amino acids B-5 and nitroethenes B-2.

TABLE 1 # structure t_(ret) [min] [M + H]⁺ HPLC method B-6a

1.21 440 A B-6b

1.21 440 A B-6c

1.09 441 A B-6d

1.09 441 A B-6e

1.13 441 A B-6f

1.13 441 A B-6g

1.17 422 A B-6h

1.17 422 A B-6i

1.25 458 A B-6j

1.25 458 A

Synthesis of Intermediates B-7 Experimental Procedure for the Synthesisof B-7a (Method E)

To a solution of cyclopropanecarbaldehyde (1.7 mL, 22.7 mmol) in AcOH(19.5 mL) is added intermediate B-6a (1.60 g, 3.8 mmol) and the reactionmixture is stirred for 15 min. Sodium triacetoxyborohydride (1.34 g, 6.3mmol) is added and the reaction mixture is stirred overnight. Water isadded to the reaction mixture and it is extracted with EtOAc. Thecombined organic layer is dried (MgSO₄), filtered, concentrated in vacuoand the crude product B-7a is purified by chromatography if necessary.

The following intermediates B-7 (table 2) are available in an analogousmanner starting from different intermediates B-6 and aldehydes.

TABLE 2 # structure t_(ret) [min] [M + H]⁺ HPLC method B-7a

1.37 494 A B-7b

1.37 494 A B-7c

1.44 508 A B-7d

1.43 496 A B-7e

1.47 510 A B-7f

1.37 482 A B-7g

1.32 468 A B-7h

1.28 498 A B-7i

1.47 574 A B-7j

1.45 574 A B-7k

495 1.29 A B-7l

495 1.29 A B-7m

1.29 495 A B-7n

1.37 476 A B-7o

1.37 476 A B-7p

1.38 512 A B-7q

1.38 512 A B-7r

0.80 575 E B-7s

0.80 575 E

Synthesis of Intermediates B-3 Experimental Procedure for the Synthesisof B-3a (Method A)

6-Chloroisatin S-1a (5 g, 27.0 mmol),1-(3-chloro-2-fluoro-phenyl)-2-nitroethene B-2a (5.5 g, 27.0 mmol) andamino acid B-1a (4.4 g, 27.0 mmol) are refluxed in MeOH for 4 h. Thereaction mixture is concentrated in vacuo and purified bycrystallization or chromatography if necessary.

The following intermediates B-3 (table 3) are available in an analogousmanner starting from different annulated 1H-pyrrole-2,3-diones S-1,amino acids B-1 and nitroethenes B-2.

TABLE 3 # structure t_(ret) [min] [M + H]⁺ HPLC method B-3a

1.42 482 A B-3b

1.42 482 A

Synthesis of Intermediates B-4 Experimental Procedure for the Synthesisof B-4a (Method B)

To a solution of cyclopropanecarbaldehyde (0.64 g, 8.9 mmol) in AcOH(0.5 mL) is added intermediate B-3a (2.68 g, 4.4 mmol) and the reactionmixture is stirred for 15 min. Sodium triacetoxyborohydride (2.8 g, 13.3mmol) is added and the reaction mixture is stirred overnight. Water isadded to the reaction mixture and it is extracted with EtOAc. Thecombined organic layer is dried (MgSO₄), filtered, concentrated in vacuoand the crude product B-4a is purified by chromatography if necessary.

The following intermediates B-4 (table 4) are available in an analogousmanner starting from different intermediates B-3 and differentaldehydes.

TABLE 4 # structure t_(ret) [min] [M + H]⁺ HPLC method B-4a

1.52 536 A B-4b

1.52 536 A

Synthesis of Additional Intermediates B-7 Experimental Procedure for theSynthesis of B-7t (Method C)

To a solution of B-4a (2.38 g, 4.0 mmol) in DCM is added DIBAL (18.0 mL,18 mmol, 1.0 M in DCM) slowly at 0° C. and the reaction mixture isstirred for 1 h. To the reaction mixture is added water and saturatedaqueous potassium sodium tartrate solution and the mixture is stirredovernight at rt. The phases are separated and the aqueous phase isextracted with DCM. The combined organic layer is dried (MgSO₄),filtered, concentrated in vacuo and the crude product B-7t is purifiedby chromatography if necessary.

The following intermediates B-7 (table 5) are available in an analogousmanner starting from different intermediates B-4.

TABLE 5 # structure t_(ret) [min] [M + H]⁺ HPLC method B-7t

1.52 508 A B-7u

1.52 508 A

Synthesis of Intermediates B-8 Experimental Procedure for the Synthesisof B-8b (Method F)

To a solution of intermediate B-7b (1 g, 2.02 mmol) in ACN (20 mL) isadded NaHCO₃ (0.34 g, 4.05 mmol) and stirred for 5 min beforeDESS-MARTIN periodinan (1.72 g, 4.05 mmol) is added portionwise to themixture. The reaction mixture is stirred for additional 30 min before itis diluted with H₂O, saturated NaHCO₃ and EtOAc. The reaction mixture isextracted with EtOAc. The combined organic layer is dried (MgSO₄),filtered, concentrated in vacuo and the crude product B-8b is purifiedby chromatography if necessary.

The following intermediates B-8 (table 6) are available in an analogousmanner starting from different intermediates B-7.

TABLE 6 # structure t_(ret) [min] [M + H]⁺ HPLC method B-8a

1.45 492 A B-8b

1.46 492 A B-8c

1.48 506 A B-8d

1.50 494 A B-8e

1.55 506 A B-8f

1.46 480 A B-8g

1.39 464 A B-8h

1.35 494 A B-8i

0.91 572 B B-8j

1.53 572 A B-8k

1.37 493 A B-8l

1.37 493 A B-8m

1.34 493 A B-8n

1.42 506 A B-8o

1.42 506 A B-8p

1.46 474 A B-8q

0.84 510 B B-8r

n.a. n.a. n.a.

Synthesis of Intermediates B-10 Experimental Procedure for the Synthesisof B-10a (Method G)

A solution of 4-iodo-3-nitro-benzoic acid methyl ester B-9a (2.60 g,8.48 mmol) in THE (17 mL) is cooled to −50° C. and phenylmagnesiumchloride (4.05 mL, 8.09 mmol, 2 M) is added dropwise and the reactionmixture is stirred for additional 30 min at −50° C. A solution ofintermediate B-8b (1.90 g, 3.85 mmol) in THE (7.7 mL) is added to thereaction mixture dropwise at −50° C. and the reaction mixture is stirredfor additional 15 min at the same temperature. The reaction mixture isslowly warmed to rt and stirred for additional 2 h before saturatedaqueous KHSO₄ solution and EtOAc is added. The reaction mixture isextracted with EtOAc. The combined organic layer is dried (MgSO₄),filtered, concentrated in vacuo and the crude product B-10a is purifiedby chromatography. B-10a is obtained as a mixture of two diastereomerswhich is used for the next step without separation.

The following intermediates B-10 (table 7) are available in an analogousmanner starting from different intermediates B-8 and different iodidesB-9.

TABLE 7 # structure t_(ret) [min] [M + H]⁺ HPLC method B-10a

1.58 673 A B-10b

1.63 687 A B-10c

1.61 675 A B-10d

1.62 687 A B-10e

1.57 659 A B-10f

1.53 647 A B-10g

1.49 675 A B-10h

1.63 753 A B-10i

1.61 687 A B-10j

1.62 687 A B-10k

1.52 703 A B-10l

1.58 709 A B-10m

1.58 709 A B-10n

1.54 673 A B-10o

1.66 698 A B-10p

1.62 767 A B-10q

1.51 674 A B-10r

1.51 674 A B-10s

1.48 674 A B-10t

n.a. n.a. — B-10u

n.a. n.a. —

Synthesis of Intermediates B-9 Experimental Procedure for the Synthesisof B-9b

To a solution of 4-amino-2-methyl-3-nitro-benzoic acid methyl ester (2.4g, 11.0 mmol) in HCl (25 mL) at 0° C. is slowly added sodium nitrite andthe mixture is stirred for 30 min at the same temperature. Potassiumiodide (5.7 g, 34.0 mmol) is added portionwise at 0° C. and the mixtureis stirred at rt for 1 h. To the reaction mixture is added water andEt₂O. The phases are separated and the aqueous phase is extracted withEt₂O. The combined organic layer is dried (MgSO₄), filtered,concentrated in vacuo and the crude product B-9b is purified bychromatography if necessary.

Experimental Procedure for the Synthesis of B-9c

To a solution of 2-hydroxy-4-iodo-3-nitro-benzoic acid methyl ester (1.0g, 3.1 mmol) is added potassium carbonate (1.3 g, 9.3 mmol) and methyliodide (0.4 mL, 6.2 mmol) at rt. The reaction mixture is stirred at rtfor 4 h. Water is added to the mixture and the formed solid is filteredand dried to yield intermediate B-9c.

TABLE 8 # structure t_(ret) [min] [M + H]⁺ HPLC method B-9b

1.25 n.a. A B-9c

1.19 338 A

Synthesis of Intermediates B-11 Experimental Procedure for the Synthesisof B-11a

To a solution of intermediate B-10a (1 g, 1.49 mmol) in THE (10 mL) isadded NaHCO₃ (0.34 g, 1.49 mmol) and stirred for 5 min beforeDESS-MARTIN periodinan (1.26 g, 2.97 mmol) is added portionwise to themixture. The reaction mixture is stirred for additional 2 h at rt beforeit is diluted with H₂O, saturated NaHCO₃ and EtOAc. The reaction mixtureis extracted with EtOAc. The combined organic layer is dried (MgSO₄),filtered, concentrated in vacuo and the crude product B-11a is purifiedby chromatography if necessary.

The following intermediates B-11 (table 9) are available in an analogousmanner starting from different intermediates B-10.

TABLE 9 # structure t_(ret) [min] [M + H]⁺ HPLC method B-11a

1.57 671 A B-11b

1.66 685 A B-11c

1.64 673 A B-11d

1.65 687 A B-11e

1.60 659 A B-11f

1.56 645 A B-11g

1.50 675 A B-11h

1.63 751 A B-11i

1.63 685 A B-11j

1.62 685 A B-11k

1.57 701 A B-11l

1.54 701 A B-11m

1.54 701 A B-11n

1.56 671 A B-11o

1.70 687 A B-11p

1.65 765 A B-11q

1.55 672 A B-11r

1.55 672 A B-11s

0.89 672 J B-11t

0.98 699 E B-11u

0.98 699 E

Synthesis of Intermediates B-12 Experimental Procedure for the Synthesisof B-12a (Method I)

To a solution of intermediate B-11a (1.10 g, 1.60 mmol) in MeOH (6 mL)and DCM (9 mL) in an autoclave is added a catalytic amount of RANEYnickel and the reaction mixture is stirred for 24 h under an atmosphereof hydrogen (8 bar). Additional RANEY nickel is added and the reactionmixture is stirred for additional 24 h under an atmosphere of hydrogen(8 bar). The reaction mixture is filtered (Celite©) and the solvents areremoved in vacuo. The residue is dissolved in EtOAc and saturatedaqueous NaHCO₃ solution is added. The reaction mixture is extracted withEtOAc. The combined organic layer is dried (MgSO₄), filtered,concentrated in vacuo and the crude product B-12a is purified bychromatography if necessary. Intermediate B-12a is obtained as a mixtureof two diastereomers which is used for the next step without furtherseparation.

The following intermediates B-12 (table 10) are available in ananalogous manner starting from different intermediates B-11.

TABLE 10 # structure t_(ret) [min] [M + H]⁺ HPLC method B-12a

1.52 595 A B-12b

1.59 609 A B-12c

1.58 597 A B-12d

1.62 611 A B-12e

1.53 583 A B-12f

1.48 568 A B-12g

1.40 599 A B-12h

1.56 675 A B-12i

1.55 609 A B-12j

1.58 609 A B-12k

1.42 625 A B-12l

1.55 625 A B-12m

1.55 625 A B-12n

1.50 595 A B-12o

1.63 611 A B-12p

1.61 689 A B-12q

1.48 596 A B-12r

1.48 596 A B-12s

1.44 596 A B-12t

1.61 623 A B-12u

1.61 623 A

Synthesis of Compounds (Ia) According to the Invention ExperimentalProcedure for the Synthesis of Ia-1 (Method J)

To a solution of intermediate B-12a (329 mg, 0.65 mmol) in DCM (7 mL) isadded a solution of Oxone© (793 mg, 1.29 mmol) in H₂O (7 mL) at 0° C.dropwise. The biphasic reaction mixture is stirred vigorously for 20 minat 0° C. and for additional 2 h at rt. The reaction mixture is dilutedwith H₂O and is extracted with DCM. The combined organic layer is dried(MgSO₄), filtered, concentrated in vacuo and the crude product ispurified by chromatography which gives compound Ia-1.

The following compounds (Ia) (table 11) are available in an analogousmanner starting from different intermediates B-12.

TABLE 11 # structure t_(ret) [min] [M + H]⁺ HPLC method Ia-1

1.60 591 A Ia-2

1.67 605 A Ia-3

1.64 593 A Ia-4

1.59 579 A Ia-5

1.54 565 A Ia-6

1.49 595 A Ia-7

1.59 671 A Ia-8

1.64 605 A Ia-9

1.63 605 A Ia-10

1.50 621 A Ia-11

1.58 621 A Ia-12

1.58 621 A Ia-13

1.59 591 A Ia-14

1.69 685 A Ia-15

1.67 607 A Ia-16

1.66 607 A Ia-17

1.48 592 A Ia-18

1.48 592 A Ia-19

1.48 592 A

Synthesis of Additional Compounds (Ia) According to the InventionExperimental Procedure for the Synthesis of Ia-20 (Method J+Method K)

* The location of overoxidation/N-oxid formation is not entirely clear.B-13a as depicted seems to be probable.

To a solution of intermediate B-12j (417 mg, 0.68 mmol) in DCM (10 mL)is added a solution of Oxone© (841 mg, 1.37 mmol) in H₂O (7 mL) at 0° C.dropwise. The biphasic reaction mixture is stirred vigorously for 20 minat 0° C. and for additional 6 h at rt. The reaction mixture is dilutedwith H₂O and extracted with DCM. The combined organic layer is dried(MgSO₄), filtered, concentrated in vacuo which gives a crude mixture ofIa-20 and an oxidized form B-13a (M+H=621). This mixture is dissolved inMeCN (4.2 mL) and bis(pinacolato)diborone (326 mg, 1.28 mmol) is added.The reaction mixture is heated under microwave irradiation to 100° C.for 30 min. The reaction mixture is diluted with H₂O and extracted withDCM. The combined organic layer is dried (MgSO₄), filtered, concentratedin vacuo and the crude product is purified by chromatography which givescompound Ia-20.

The following overoxidized compounds B-13 (table 12) are available in ananalogous manner starting from different intermediates B-12 and can bereduced to additional compounds (Ia) (table 13).

TABLE 12 # structure t_(ret) [min] [M + H]⁺ HPLC method B-13a

0.96 621 C B-13b

0.89 565 C B-13c

0.94 611 C B-13d

0.95 635 E B-13e

0.95 635 E

TABLE 13 # structure t_(ret) [min] [M + H]⁺ HPLC method Ia-20

1.66 605 A Ia-21

1.54 565 A Ia-22

1.46 595 A Ia-23

1.01 619 E Ia-24

1.01 619 E

Synthesis of Further Compounds (Ia) Via Ester SaponificationExperimental Procedure for the Synthesis of Ia-25

Ia-1 (405 mg, 0.69 mmol) is dissolved in THE (30 mL) and aq. NaOHsolution (2 mL, 8 M) is added. The reaction mixture is stirred at 70° C.for 8 h. After acidification with 2 M aq. HCl and extraction with EtOActhe organic phase is dried with MgSO₄. Purification with reversed phaseHPLC leads to pure Ia-25.

The following compounds (Ia) (table 14) are available in an analogousmanner starting from initially obtained compounds (Ia).

TABLE 14 # structure t_(ret) [min] [M + H]⁺ HPLC method Ia-25

1.04 577 A Ia-26

1.10 591 A Ia-27

1.09 579 A Ia-28

1.14 593 A Ia-29

1.06 565 A Ia-30

1.00 551 A Ia-31

0.95 581 A Ia-32

1.11 657 A Ia-33

1.07 591 A Ia-34

1.03 591 A Ia-35

1.04 607 A Ia-36

1.04 607 A Ia-37

1.04 607 A Ia-38

1.01 577 A Ia-39

1.09 593 A Ia-40

1.13 671 A Ia-41

1.02 578 A Ia-42

1.02 578 A Ia-43

1.02 578 A Ia-44

1.07 605 A Ia-45

1.07 605 A

Synthesis of Further Compounds (Ia) Via Amidation Experimental Procedurefor the Synthesis of Ia-46

Ia-26 (10 mg, 0.02 mmol) is dissolved in anhydrous THE (1 mL) and HATU(8 mg, 0.02 mmol) is added at rt. After addition of DIPEA (3.4 mg, 0.03mmol) the reaction mixture is allowed to stir at rt for 15 min.1-Amino-2-methylpropan-2-ol (2 M in THF, 1.5 mg, 0.02 mmol) is added andthe reaction is allowed to stir for additional 60 min. The crudereaction mixture is submitted to reversed phase column chromatographyyielding pure Ia-46.

The following compounds (Ia) (Table 15) are available in an analogousmanner starting from initially obtained compounds (Ia).

TABLE 15 # structure t_(ret) [min] [M + H]⁺ HPLC method Ia-46

1.43 662 A Ia-47

1.49 630 A Ia-48

1.51 692 A Ia-49

1.46 692 A Ia-50

1.22 594 A Ia-51

1.35 621 A Ia-52

1.50 618 A Ia-53

1.33 620 A Ia-54

1.52 740 A Ia-55

1.51 728 A Ia-56

1.49 684 A Ia-57

1.54 698 A

Synthesis of Starting Material S-1 Experimental Procedure for theSynthesis of S-1b

3,3-Dibromo-6-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (7.6 g,23.3 mmol) is suspended in acetonitrile (500 mL) and water (25 mL).AgNO₃ (8.9 g, 52.7 mmol) is added and the reaction mixture is stirred atrt for 1 h. Acetonitrile is removed under reduced pressure and EtOAc isadded. The phases are separated and the organic layer is dried withMgSO₄. Removal of the solvents gives pure6-chloro-1H-pyrrolo[2,3-b]pyridine-2,3-dione S-1b.

Synthesis of Intermediates B-15 Experimental Procedure for the Synthesisof B-15a

To a solution of B-14a (1 eq.) in toluene is added Ac₂O (1.05 eq.)dropwise at reflux and the mixture is stirred at reflux for severalminutes. The product B-15a can be crystallized out of the mixture bycooling down and further dilution.

The following intermediates B-15 (table 15-1) are available in ananalogous manner starting from different anilines B-14.

TABLE 15-1 # structure [M + H]⁺ B-15a

194 B-15b

208 B-15c

224 B-15d

224 B-15e

194 B-15f

208

Synthesis of Intermediates B-16 Experimental Procedure for the Synthesisof B-16a

To a solution of B-15a (1 eq.) in AcOH are added TsOH monohydrate (0.5eq.) and Pd(OAc)₂ (0.03 eq.). The mixture is heated up to 75-80° C. andNBS (1.1 eq.) is added in portions. After stirring at 75-80° C. for afew minutes, the solution is cooled down and water is added. The productB-16a can be isolated by filtration.

The following intermediates B-16 (table 15-2) are available in ananalogous manner starting from different acetamides B-15.

TABLE 15-2 # structure [M + H]⁺ B-16a

273 B-16b

287 B-16c

303 B16-d

303 B-16e

273 B-16f

287

Synthesis of Intermediates B-17 Experimental Procedure for the Synthesisof B-17a

To a suspension of B-16a (1 eq.) in DMSO are added Boc-prop-2-ynyl-amine(1.3 eq.), CuI (0.02 eq.), Pd₂(dba)₃ (0.01 eq.), [(tBu)₃P]BF₄ (0.04 eq.)and DIPA (5 eq.). The mixture is stirred at room temperature for 3 days.After cooling down the suspension and adding water the product B-17a canbe isolated by filtration.

The following intermediates B-17 (table 15-3) are available in ananalogous manner starting from different bromo acetamides B-16.

TABLE 15-3 # structure [M + H]⁺ B-17a

347 B-17b

361 B-17c

377 B-17d

377 B-17e

347 B-17f

361

Synthesis of Intermediates B-18 Experimental Procedure for the Synthesisof B-18a

To a solution of B-17a (1 eq.) in AcOH is added Pd(OAc)₂ (0.02 eq.) andthe mixture is stirred at room temperature until complete consumption ofB-17a. Subsequently, water and conc. HCl are added. After the cleavageof the Boc group (decreasing C02 formation), the mixture is heated up to70° C. and stirred at this temperature for 3 days. The product B-18a canbe crystallized from the reaction mixture by cooling down.

The following intermediates B-18 (table 15-4) are available in ananalogous manner starting from different phenyl alkynyls B-17.

TABLE 15-4 # structure [M + H]⁺ B-18a

209 B-18b

223 B-18c

239 B-18d

239 B-18e

209 B-18f

223

Experimental Procedure for the Synthesis of B-18q

To a suspension of B-18a (1 eq.) in MeOH is added SOCl₂ (3 eq.) dropwiseat 60° C. and the mixture is stirred overnight at this temperature.After cooling down to room temperature the mixture is filtrated over anactivated carbon filter and the solvents are afterwards removed underreduced pressure. The product B-18g can be purified by crystallization.

The following benzoic acid ester intermediates B-18 (table 15-5) areavailable in an analogous manner starting from different benzoic acidsB-18 initially obtained.

TABLE 15-5 # structure [M + H]⁺ B-18g

223 B-18h

237 B-18i

253 B-18j

253 B-18k

223 B-18l

237

Synthesis of Intermediates B-19 Experimental Procedure for the Synthesisof B-19a

To a suspension of B-18g (1 eq.) in MeOH is added 6-chloroisatin S-1a(1.1 eq.), AcOH (2.4 eq.) and TEA (2 eq.). After 3 days of stirring atroom temperature the product B-19a can be filtrated.

The following imine intermediates B-19 (table 15-6) are available in ananalogous manner starting from different benzoic acid esters B-18.

TABLE 15-6 # structure [M + H]⁺ B-19a

387 B-19b

400 B-19c

416 B-19d

416 B-19e

387 B-19f

400

Synthesis of Intermediates B-20 Experimental Procedure for the Synthesisof B-20a

1-Chloro-2-fluoro-3-(E)-2-nitro-vinyl)-benzene (1.1 eq.) is suspended intoluene and water and heated up. Subsequently, the imine B-19a (1 eq.)and 1-methylpyrrolidine (4 eq.) are added. The mixture is stirred underreflux. The reaction is quenched at 0° C. by the addition of AcOH. Theorganic phase is washed with water and saline and is then added dropwiseto nHep. The product B-20a can be purified by crystallization.

If a chiral separation of the enantiomers of the racemic mixture ofintermediate B-20a is desired then a crystallization with chiral acidslike e.g. (S,S)-(+)-2,3-dibenzoyl-D-tartaric acid,(S,S)-(+)-2,3-p-toluyl-D-tartaric acid, (1S)-(+)camphor-10-sulfonicacid, (1R)-(−)camphor-10-sulfonic acid, (R)-(−)-mandelic acid,L-pyroglutamic acid or (S,S)-D-(−)-tartaric acid can be considered. Theuse of (1R)-(−)camphor-10-sulfonic acid is preferred.

The following intermediates B-20 (table 15-7) are available in ananalogous manner starting from different imines B-19.

TABLE 15-7 [M + # structure H]⁺ B-20a

587 B-20b

601 B-20c

617 B-20d

617 B-20e

587 B-20f

601 B-20g

587 B-20h

601 B-20i

617 B-20j

617 B-20k

587 B-20l

601

Synthesis of Intermediates B-22 Experimental Procedure for the Synthesisof B-22a

To a solution of B-20g (1 eq.) in MeTHF is added water and Pt/C (15 wt%). The mixture is hydrogenated for 3 days at 30° C. under 70 bar H₂pressure. After complete conversion to B-21a, VO(acac)₂ (0.11 eq.) isadded and the mixture is further hydrogenated at 30° C. at 70 bar for 2days. The catalysts are filtered out and the solvent is removed underreduced pressure. The product B-22a is dissolved in toluene and byadding 2 M H₂SO₄ (1.11 eq.) the sulfate of B-22a can be precipitated.

The reaction sequence B-20→B-21→B-22 is also possible with racemic B-20(if there is no chiral separation of B-20). In this case chiralseparation can also be performed on the stage of B-22 by acrystallization with chiral acids like e.g.(S,S)-(+)-2,3-dibenzoyl-D-tartaric acid,(S,S)-(+)-2,3-p-toluyl-D-tartaric acid, (1S)-(+)camphor-10-sulfonicacid, (R)-(−)-mandelic acid, L-pyroglutamic acid, (S,S)-D-(−)-tartaricacid, (S)-(−)-L-malic acid or L-(+)-lactic acid((S,S)-(+)-2,3-p-toluyl-D-tartaric acid is preferred).

The following intermediates B-21 and B-22 (table 15-8) are available inan analogous manner starting from different intermediates B-20.

TABLE 15-8 # structure [M + H]⁺ B-21a

557 B-21b

571 B-21c

587 B-21d

587 B-21e

557 B-21f

571 B-22a

541 B-22b

555 B-22c

571 B-22d

571 B-22e

541 B-22f

555

Synthesis of Intermediates B-23 Experimental Procedure for the Synthesisof B-23a

To a suspension of B-22a (1 eq.) in CH₂Cl₂ and water (4:1) is addedNa₂WO₄ dihydrate (0.01 eq.) and H₂O₂ solution (30% in water, 2.5 eq.)and the mixture is stirred under reflux for 2 h. Then a solution ofK₂CO₃ (2 eq.) in water is added and the CH₂Cl₂ is removed under reducedpressure. The solid product B-23a can be purified by slurrying in anappropriate solvent.

The following intermediates B-23 (table 15-10) are available in ananalogous manner starting from different intermediates B-22.

TABLE 15-9 # structure [M + H]⁺ B-23a

537 B-23b

551 B-23c

567 B-23d

567 B-23e

537 B-23f

551

Compounds (Ib) General Reaction Scheme and Summary of the SynthesisRoute

Novel compounds of structure (Ib) can be prepared stepwise by asynthesis route starting from protected amino acids A-1 (scheme 3).First, an acylation reaction using acrylic acid derivatives A-2 yieldscompounds of structure A-3 (method A). Acrylic acids which are notdirectly available can be obtained e.g. by WITTIG reaction (D-1, D-2,not depicted in scheme 3). Treatment of intermediates A-3 under acidicconditions, preferentially with trifluoro acetic acid, forms freeunsaturated amino acid derivatives A-4 (method B). A decarboxylative1,3-dipolar cycloaddition of A-4 and isatin derivatives S-1 yieldscycloadducts A-5 as a mixture of diastereo isomers and builds up thespiro system (method C). The diastereomers can be separated, e.g. byHPLC or SFC. The obtainable racemic mixture can be resolved by chiralSFC separation or at any later stage in the synthesis. Also all othermeans known for separation of enantiomers can be applied here or afterany later synthetic step herein described, e.g. crystallisation, chiralresolution, chiral HPLC etc. (see also Enantiomers, racemates, andresolutions, Jean Jacques, André Collet, Samuel H Wilen John Wiley andSons, N Y, 1981).

Alternatively cycloadduct A-5 can be prepared by a 1,3-dipolarcycloaddition of amine A-8 and isatin derivatives S-1 as a mixture ofdiastereo isomers (method E). Intermediates A-8 can be prepared in onepot from amines A-6 by an acylation reaction using acrylic acidderivatives A-2 and subsequent cleavage of the Boc-protecting group byaddition of HCl (method D).

Intermediates A-5 can be reacted with aldehydes or ketones in areductive amination reaction to give intermediates A-9 (introduction ofR¹, method F). Alternatively, an alkylation, addition, acylation orsulfonylation reaction can be performed with A-5 to additionalintermediates of formula A-9. Subjecting intermediates A-9 tometal-catalyzed cross coupling reactions (e.g. BUCHWALD amidation) withsubstituted nitro (hetero)aryl halides A-10 gives intermediates A-11(method G). A reductive cyclization of intermediates A-11 by treatmentwith iron powder in acetic acid, or alternative reducing agents givescompounds (Ib).

Compounds (Ib) which are initially obtained can be derivatized inoptional derivatization steps not explicitly depicted in the schemes inall residues, especially in R⁴, if they carry functional groups, thatcan be further modified such as e.g. halogen atoms, amino and hydroxygroups (including cyclic amines), carboxylic acid or ester functions,nitrils etc. to further compounds (Ia) by well-established organicchemical transformations such as metal-catalyzed cross couplingreactions, acylation, amidation, addition, reduction or (reductive)alkylation or cleavage of protecting groups. These additional steps arenot depicted in the general schemes. Likewise, it is also possible toinclude these additional steps in the synthetic routes depicted in thegeneral schemes, i.e. to carry out derivatization reactions withintermediate compounds. In addition, it may also be possible thatbuilding blocks bearing protecting groups are used, i.e. further stepsfor deprotection are necessary.

Alternatively, novel compounds of structure (Ib) can be preparedstepwise by a synthesis route starting from intermediates A-5 (scheme4). Intermediates A-5 are treated with acetic anhydride in formic acidto generate intermediates A-12 (method I). Subjecting intermediates A-12to metal-catalyzed cross coupling reactions (e.g. BUCHWALD amidation)with substituted nitro (hetero)aryl halides A-10 gives intermediatesA-13 (method G). A reductive cyclization of intermediates A-13 bytreatment with iron powder in acetic acid, or alternative reducingagents, gives intermediates A-14. Deformylation mediated by hydrochloricacid in MeOH gives intermediates A-15 (method J). Intermediates A-15 canbe reacted with aldehydes or ketones in a reductive amination reactionto give compounds (Ib) (introduction of R¹, methods K and L).Alternatively, an alkylation, addition, acylation or sulfonylationreaction can be performed with A-15 to additional compounds of formula(Ib).

Alternatively, novel compounds of structure (Ib) can be preparedstepwise by a synthesis route starting from diamino (hetero)aryls A-16(scheme 5). First, an acylation reaction using acrylic acid derivativesA-2 yields compounds of structure A-17 (method M). Acrylic acids whichare not directly available can be obtained e.g. by WITTIG reaction (D-1,D-2, not depicted in scheme 5). Treatment of intermediates A-17 withhydrochloric acid gives condensed imidazole (e.g. benzimidazole)intermediates A-18 (method N). Alkylation of intermediate A-18 withbromides A-19, or alternative alkylating agents, gives intermediatesA-20 (method O). Treatment of intermediates A-20 under acidicconditions, preferentially with trifluoro acetic acid, forms freeunsaturated amine derivatives A-21 (method P). A 1,3-dipolarcycloaddition of A-21 and isatin derivatives S-1 yields cycloadductsA-15 as a mixture of diastereo isomers and builds up the spiro system(method Q). Intermediates A-15, as described above, can be reacted withaldehydes or ketones in a reductive amination reaction to give compounds(Ib) (introduction of R¹, methods K and L). Alternatively, analkylation, addition, acylation or sulfonylation reaction can beperformed with A-15 to additional compounds of formula (Ib).

Compounds (Ib) have been tested for their activity to affect MDM2-p53interaction in their racemic form or alternatively as the enantiopureform. Each of the two enantiomers of a racemic mixture may have activityagainst MDM2 although with a different binding mode.

Enantiopure compounds are marked with the label “Chiral”. Compoundslisted in any table below that are labeled “Chiral” (both intermediatesas well as compounds (Ib) according to the invention) can be separatedby chiral SFC chromatography from their enantiomer or are synthesizedfrom enantiopure starting material which is separated by chiral SFC.

EXAMPLE

Structure A defines the racemic mixture of compounds with structure Band C, i.e. structure A encompasses two structures (compounds B and C),whereas structures B and C, respectively, are enantiopure and onlydefine one specific compound. Thus, formulae (Ib) and (Ib*)

with a set of specific definitions for groups R¹ to R⁴, R⁷, V, W, X, Y,n, r and q represent the racemic mixture of two enantiomers (→(Ib);structure A above is one specific example of such a racemic mixture) ora single enantiomer (→(Ib*); structure B above is one specificenantiomer), unless there are additional stereocenters present in one ormore of the substituents. The same definition applies to syntheticintermediates.

Synthesis of Intermediates A-2 Experimental Procedure for the Synthesisof A-2a

2-Chloro-3-fluoro-pyridine-4-carbaldehyde D-1a (1 g, 6.3 mmol) isdissolved in anhydrous MTBE (10 mL) under an argon atmosphere. Methyl(triphenylphosphoranylidene)acetate (2.1 g, 6.3 mmol) is added in oneportion and the reaction mixture is stirred at rt for 1 h. Water andEtOAc is added and the phases are separated. The organic phase is driedwith MgSO₄, filtered and the solvent is removed under reduced pressure.The residue is purified by reversed phase column chromatography givingpure (E)-3-(2-chloro-3-fluoro-pyridin-4-yl)-acrylic acid methyl esterD-2a.

D-2a (780 mg, 3.6 mmol) is dissolved in THE (3 mL) and 2 M NaOH is added(3.6 mL, 7.2 mmol). The reaction mixture is stirred at 60° C. for 1 hbefore it is quenched by the addition of 2 M HCl. Extraction with EtOAcand subsequent drying of the organic phase using MgSO₄ yields crude A-2aupon removal of the solvents under reduced pressure. Reversed phasecolumn chromatography gives pure(E)-3-(2-chloro-3-fluoro-pyridin-4-yl)-acrylic acid A-2a.

Further building blocks A-2 are available in an analogous mannerstarting from different carbaldehydes D-1.

TABLE 16 t_(ret) HPLC # structure [min] [M + H]⁺ method A-2a

0.0 202 A

Synthesis of Intermediates A-3 (Method A) Experimental Procedure for theSynthesis of A-3a

3-Chloro-2-fluoro cinnamic acid A-2b (10.3 g, 50.67 mmol) is suspendedin anhydrous DMF (300 mL) at 0° C. and DIPEA (19.5 mL, 120.65 mmol) andHATU (20.39 g, 53.09 mmol) are added to the reaction mixture. Thereaction mixture is stirred at 0° C. for 30 min. A solution of(S)-4-amino-2-tert-butoxycarbonylamino-butyric acid tert-butyl esterhydrochloride A-1a (15.0 g, 48.26 mmol) in DMF (100 mL) is addeddropwise over a period of 15 min. The reaction mixture is stirred foradditional 60 min and sat. aq. NH₄Cl solution is added. Deionized wateris added and the mixture is extracted with a 1:1 mixture of EtOAc andcyclohexane. The layers are separated and the organic phase is washedwith deionized water and dried with MgSO₄. The solvents are removedunder reduced pressure and(S)-2-tert-butoxycarbonylamino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid tert-butyl ester A-3a is used without further purification.

The following intermediates A-3 (table 17) are available in analogousmanner starting from different acrylic acids A-2 and protected aminoacids A-1.

TABLE 17 # structure t_(ret) [min] [M + H]⁺ HPLC method A-3a

1.56 [M + H-Boc]⁺ 357 A A-3b

1.56 [M + H-Boc]⁺ 357 A A-3c

0.82 443 G A-3d

0.82 443 G A-3e

n.a. n.a. A-3f

n.a. n.a. A-3g

1.44 466 A A-3h

1.44 466 A A-3i

n.a. n.a. A-3j

n.a. n.a.

Synthesis of Intermediates A-4 (Method B) Experimental Procedure for theSynthesis of A-4a

(S)-2-tert-Butoxycarbonylamino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid tert-butyl ester A-3a (22.4 g, 48.9 mmol) is dissolved in DCM (150mL). TFA (35 mL) is added at 0° C. and the reaction mixture is slowlywarmed to rt. The reaction mixture is heated to reflux for 24 h. Beforeit is concentrated in vacuo, aq. NaOH (4 M) is added at 0° C. until a pHof 12 is reached. Addition of aq. HCl (2 M) results in the formation ofa precipitate at pH 6-7 which is filtered off. The solid residue(S)-2-amino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid hydrochloride A-4a is washed with water and acetonitrile and driedat 50° C. under reduced pressure.

The following intermediates A-4 (table 18) are available in an analogousmanner starting from different intermediates A-3.

TABLE 18 # structure t_(ret) [min] [M + H]⁺ HPLC method A-4a

0.91 301 A A-4b

0.91 301 A A-4c

0.63 287 A A-4d

0.63 287 A A-4e

0.21 288 A A-4f

0.21 288 A A-4g

1.40 302 M A-4h

1.40 302 M

Synthesis of Intermediate A-5 (Method C) Experimental Procedure for theSynthesis of A-5a and A-5c

(S)-2-Amino-4-[(E)-3-(3-chloro-2-fluoro-phenyl)-acryloylamino]-butyricacid A-4a (0.34 g, 1.13 mmol), 6-chloro-1H-indole-2,3-dione S-1a (2.1 g,1.13 mmol) and ground, activated 4 A molecular sieves are suspended inanhydrous MeOH (15 mL) in a microwave vial. The reaction vessel issealed with Teflon caps and irradiated for 30 min at a final temperatureof 100° C. After cooling to rt, the crude mixture is filtered over a padof Celite© and solvents are removed under reduced pressure. The crudereaction mixture is purified by reversed phase HPLC which givesdiastereomers A-5a and A-5c.

The following intermediates A-5 (Table 19) are available in analogousmanner starting from different intermediates A-4 and S-1.

TABLE 19 # structure t_(ret) [min] [M + H]⁺ HPLC method A-5a

0.49 420 G A-5b

0.49 420 G A-5c

0.45 420 G A-5d

0.53 512 G A-5e

0.53 512 G A-5f

0.93 421 A A-5g

0.93 421 A A-5h

0.89 421 A A-5i

0.99 406 A A-5j

0.99 406 A A-5k

0.99 406 A A-5l

0.93 421 A A-5m

0.93 421 A A-5n

0.50 451 G A-5o

0.50 451 G A-5p

0.91 421 A A-5q

0.91 421 A

Synthesis of Intermediates A-8 (Method D) Experimental Procedure for theSynthesis of A-8a

(E)-3-(4-Chloro-thiophen-2-yl)-acrylic acid A-2c (554 mg, 2.94 mmol) issuspended in anhydrous DMF (5 mL) at 0° C. and DIPEA (1.14 g, 129.3mmol) and HATU (1.34 g, 3.52 mmol) are added to the reaction mixture.The mixture is stirred at 0° C. for 30 min. A solution of(2-amino-ethyl)carbamic acid tert-butyl ester A-6a (470 mg, 2.94 mmol)in DMF (1 mL) is added dropwise over a period of 15 min. The reactionmixture is stirred for additional 30 min. Concentrated HCl (2.89 g,29.37 mmol) is added and the mixture is heated to 90° C. and stirred for90 min. Sodium hydroxide (8 N in H₂O) is added until a pH of 12 isreached and the mixture is extracted with EtOAc. The layers areseparated and the organic phase is washed with deionized water and driedwith MgSO₄. The solvents are removed under reduced pressure and thecrude reaction mixture is purified by reversed phase HPLC if necessaryto obtain intermediate A-8a.

The following intermediates A-8 (table 20) are available in an analogousmanner starting from different acrylic acids A-2 and amines A-6.

TABLE 20 # structure t_(ret) [min] [M + H]⁺ HPLC methold A-8a

0.28 231 G A-8b

0.29 231 G A-8c

0.86 243 A A-8d

0.86 257 A

Synthesis of Additional Intermediates A-5 (Method E) ExperimentalProcedure for the Synthesis of A-5r and A-5t

(E)-N-(2-Amino-ethyl)-3-(4-chloro-thiophen-2-yl)acrylamide A-8a (0.37 g,1.60 mmol), 6-chloro-1H-indole-2,3-dione S-1a (306 mg, 1.60 mmol) andtriethylamine (162 mg, 1.60 mmol) are suspended in anhydrous NMP (12 mL)in a microwave vial. The reaction vessel is sealed with a Teflon cap andirradiated for 30 min at a final temperature of 110° C. After cooling tort the solvents are removed under reduced pressure. The product is usedcrude for the next step or purified by reversed phase HPLC which givesdiastereomers A-5r and A-5t.

The following intermediates A-5 (table 21) are available in analogousmanner starting from different intermediates S-1 and A-8.

TABLE 21 # structure t_(ret) [min] [M + H]⁺ HPLC method A-5r

0.47 394 G A-5s

0.47 394 G A-5t

0.47 394 G A-5u

0.47 394 G A-5v

0.39 394 A A-5w

0.39 394 A A-5x

0.39 394 A A-5y

0.39 394 A A-5z

0.99 406 A A-5aa

0.99 406 A A-5ab

0.80 406 K A-5ac

0.80 406 K A-5ad

0.49 420 G A-5ae

0.49 420 G A-5af

0.45 420 G

Synthesis of Intermediates A-9 (Method F) Experimental Procedure for theSynthesis of A-9a

A-5a (120 mg, 0.29 mmol) and isobutyraldehyde (62 mL, 0.86 mmol) aredissolved in AcOH (5 mL), and sodium triacetoxyborohydride (0.30 g, 1.43mmol) is added. The reaction mixture is stirred at rt for 30 min andanother portion of sodium triacetoxyborohydride (0.30 g, 1.43 mmol) isadded and stirring is continued for additional 30 min before deionizedwater is added. EtOAc is added and the phases are separated. Afterwashing with water, the organic phase is dried with MgSO₄ and thesolvents are removed under reduced pressure. If needed the product ispurified using reversed phase HPLC resulting in purified A-9a.

The following intermediates A-9 (table 22) are available in analogousmanner starting from different intermediates A-5.

TABLE 22 # structure t_(ret) [min] [M + H]⁺ HPLC method A-9a

0.74 476 G A-9b

0.74 476 G A-9c

1.29 474 A A-9d

1.29 474 A A-9e

0.73 566 G A-9f

n.a. n.a. A-9g

1.38 554 A A-9h

1.38 554 A A-9i

1.19 475 A A-9j

1.19 475 A A-9k

1.28 555 A A-9l

1.28 555 A A-9m

1.20 475 A A-9n

1.20 475 A A-9o

1.24 460 A A-9p

1.23 460 A A-9q

0.62 434 G A-9r

0.62 434 G A-9s

1.21 504 A A-9t

1.21 504 A A-9u

1.47 540 A A-9v

1.47 540 A A-9w

1.19 448 A A-9x

1.19 448 A A-9y

1.14 448 A A-9z

1.14 448 A A-9aa

1.19 448 A A-9ab

1.19 448 A A-9ac

1.14 448 A A-9ad

1.14 448 A A-9ae

1.25 541 A A-9af

1.25 541 A

Synthesis of Intermediates A-11 (Method G) Experimental Procedure forthe Synthesis of A-11a

Intermediate A-9a (400 mg, 0.84 mmol), 4-bromo-3-nitro-benzoic acidmethyl ester (A-10a, 334 mg, 0.1.26 mol), cesium carbonate (410 mg, 1.26mmol), Xantphos (97.2 mg, 0.17 mmol), and palladium trifluoroacetate(Pd(TFA)₂; 28 mg, 0.08 mmol) are suspended in 1,4-dioxane (8 mL) in amicrowave vial. The reaction is sealed and stirred at 130° C. for 5 h.After consumption of the starting material, the reaction is diluted withacetonitrile and filtered through a plug of silica. The solvents areremoved under reduced pressure yielding crude A-11a which is purified byreversed phase column chromatography if necessary.

The following intermediates A-11 (table 23) are available in ananalogous manner starting from different intermediates A-9 and A-10.

TABLE 23 # structure t_(ret) [min] [M + H]+ HPLC methold A-11a

1.00 655 G A-11b

0.93 655 D A-11c

0.88 653 G A-11d

0.90 653 D A-11e

0.90 653 D A-11f

0.91 733 G A-11g

0.91 733 G A-11h

0.91 733 G A-11i

0.80 644 G A-11j

0.80 644 G A-11k

1.53 653 A A-11l

1.53 653 A A-11m

0.95 667 D A-11n

0.85 683 G A-11o

0.97 751 G A-11p

0.97 681 D A-11q

0.90 667 G A-11r

0.91 681 G A-11s

0.96 695 G A-11t

0.96 685 D A-11u

0.92 721 G A-11v

0.89 693 G A-11w

0.89 693 G A-11x

0.91 695 G A-11y

0.91 695 G A-11z

0.85 667 G A-11aa

0.85 667 G A-11ab

0.55 640 E A-11ac

0.55 640 E A-11ad

0.89 734 F A-11ae

0.89 734 F A-11af

0.86 668 G A-11ag

0.86 668 G A-11ah

0.87 639 G A-11ai

0.88 639 G A-11aj

0.88 639 G A-11ak

0.89 639 F A-11al

0.89 639 F A-11am

0.93 677 G A-11an

0.89 653 G A-11ao

0.89 653 G A-11ap

0.87 627 G A-11aq

0.87 627 G A-11ar

0.92 707 G A-11as

0.92 707 G A-11at

0.92 707 G A-11au

0.92 707 G A-11av

0.96 737 G A-11aw

0.89 683 G A-11ax

0.89 683 G A-11ay

0.87 627 G A-11az

0.87 627 G A-11ba

0.88 627 G A-11bb

0.88 627 G A-11bc

0.80 673 G A-11bd

0.81 673 G A-11be

1.50 640 A A-11bf

1.50 640 A A-11bg

0.91 667 E A-11bh

0.93 667 E A-11bi

0.92 667 E

Synthesis of Compounds (Ib) According to the Invention (Method H)Experimental Procedure for the Synthesis of Ib-1

A-11a (533 mg, 0.8 mmol) is dissolved in acetic acid (10 mL) and ironpowder (469 mg, 8.4 mmol) is added. The suspension is heated to 130° C.overnight. After addition of EtOAc and saturated aqueous Na₂CO₃solution, the phases are separated and the organic phase is dried by theaddition of MgSO₄. Removal of the solvents yields crude Ib-1, which isof sufficient purity for the further derivatisation or purified byreversed phase column chromatography.

The following compounds (Ib) according to the invention (table 24) areavailable in an analogous manner starting from different intermediatesA-11.

TABLE 24 t_(ret) HPLC # structure [min] [M + H]⁺ method Ib-1

0.86 607 G Ib-2

0.92 607 B Ib-3

1.52 605 A Ib-4

1.52 605 A Ib-5

1.52 605 A Ib-6

0.54 685 D Ib-7

0.54 685 D Ib-8

0.54 685 D Ib-9

0.74 596 G Ib-10

0.74 596 G Ib-11

0.81 605 G Ib-12

0.81 605 G Ib-13

0.97 619 D Ib-14

0.73 635 G Ib-15

0.97 703 G Ib-16

0.87 633 G Ib-17

0.85 619 G Ib-18

0.83 633 G Ib-19

0.89 647 G Ib-20

0.96 685 D Ib-21

0.92 673 G Ib-22

0.81 645 G Ib-23

0.81 645 G Ib-24

0.80 647 G Ib-25

0.80 647 G Ib-26

0.73 619 G Ib-27

0.73 619 G Ib-28

n.a. n.a. n.a. Ib-29

n.a. n.a. n.a. Ib-30

n.a. n.a. n.a. Ib-31

n.a. n.a. n.a. Ib-32

0.84 620 G Ib-33

0.84 620 G Ib-34

0.84 591 G Ib-35

0.84 591 G Ib-36

0.84 591 G Ib-37

0.89 591 E Ib-38

0.89 591 E Ib-39

0.90 619 G Ib-40

0.87 605 G Ib-41

0.87 605 G Ib-42

0.83 579 G Ib-43

0.83 579 G Ib-44

0.92 659 G Ib-45

0.92 659 G Ib-46

0.90 659 G Ib-47

0.90 659 G Ib-48

0.97 689 G Ib-49

1.60 671 A Ib-50

1.60 671 A Ib-51

0.87 637 G Ib-52

0.87 637 G Ib-53

0.84 579 G Ib-54

0.84 579 G Ib-55

0.85 579 G Ib-56

0.85 579 G Ib-57

1.40 625 A Ib-58

1.40 625 A Ib-59

1.33 604 A Ib-60

1.33 604 A Ib-61

0.90 619 E Ib-62

0.93 619 E Ib-63

0.92 619 E

Synthesis of Intermediates A-12 (Method I) Experimental Procedure forthe Synthesis of A-12a

Intermediate A-5a (2.0 g, 4.8 mmol) is dissolved in formic acid (10 mL)and acetic anhydride is added (3.5 mL, 38.1 mmol). The reaction mixtureis stirred at 50° C. for 16 h and subsequently quenched by the additionof water. Purification by reversed phase column chromatography yieldsintermediate A-12a.

The following intermediates A-12 (Table 25) are available in ananalogous manner starting from different intermediates A-5.

TABLE 25 t_(ret) [M + HPLC # structure [min] H]⁺ method A-12a

0.99 448 A A-12b

0.99 448 A A-12c

0.49 434 G A-12d

0.49 434 G

Synthesis of Intermediates A-13 (Method G) Synthesis of A-13a

Intermediate A-13 can be synthesized from intermediate A-12 in analogyto the synthesis of intermediate A-11 from intermediate A-9 (method G,see above).

TABLE 26 HPLC # structure t_(ret) [min] [M + H]⁺ method A-13a

0.70 627 G A-13b

0.70 627 G A-13c

0.70 613 G A-13d

0.70 613 G

Synthesis of Intermediate A-14 (Method H) Synthesis of A-14a

Intermediate A-14 can be synthesized from intermediate A-13 in analogyto the synthesis of compounds (Ib) according to the invention fromintermediate A-11 (method H, see above).

TABLE 27 t_(ret) [M + HPLC # structure [min] H] ⁺ method A-14a

0.65 579 G A-14b

0.65 579 G A-14c

0.66 565 G A-14d

0.66 565 G

Synthesis of Intermediates A-15 (Method J) Experimental Procedure forthe Synthesis of A-15a

A-14a (840 mg, 1.45 mmol) is dissolved in MeOH (2 mL) and conc. HCl(37%, 500 μL) is added. The reaction mixture is heated to 100° C. for 30min. The reaction is quenched by the addition of sat. aq. NaHCO₃ andsubsequently extracted with EtOAc. Phases are separated and the organicphase is dried with MgSO₄. The solvents are removed under reducedpressure. Reverses phase column chromatography gives pure A-15a.

The following compounds A-15 (table 28) are available in an analogousmanner starting from different compounds A-14.

TABLE 28 t_(ret) [M + HPLC # structure [min] H]⁺ method A-15a

0.67 551 G A-15b

0.67 551 G A-15c

0.68 537 G A-15d

0.68 537 G

Synthesis of Intermediates A-17 (Method M) Experimental Procedure forthe Synthesis of A-17a

3-Chloro-2-fluoro cinnamic acid A-2b (3.0 g, 14.81 mmol) is suspended inanhydrous DMF (25 mL) at 0° C. and DIPEA (3.6 mL, 22.21 mmol) and HATU(5.6 g, 14.73 mmol) are added to the reaction mixture. The reactionmixture is stirred at 0° C. for 30 min. A solution of3,4-diamino-benzoic acid methyl ester A-16a (2.95 g, 17.77 mmol) in DMF(5 mL) is added dropwise over a period of 15 min. The reaction mixtureis stirred for additional 3 h and aq. K₂CO₃ solution (8 mL, 2 N) isadded. Deionized water is added and the mixture is extracted with DCM.The layers are separated and the organic phase is washed with deionizedwater and dried with MgSO₄. The solvents are removed under reducedpressure and the mixture is used without further purification or ispurified by reversed phase column chromatography to yield A-17a.

The following intermediates A-17 (table 29) are available in ananalogous manner starting from different intermediates A-2 and A-16.

TABLE 29 # structure t_(ret) [min] [M + H]⁺ HPLC method A-17a

1.16 349 A

Synthesis of Intermediate A-18 (Method N) Experimental Procedure for theSynthesis of A-18a

Intermediate A-17a (839 mg, 2.4 mmol) is dissolved in dioxane (5 mL) andconc. HCl (1.76 g) and MeOH (24 mL) is added. The resulting mixture isstirred for 15 h at 70° C. The mixture is diluted with EtOAc and aq.NaOH (4 N) is added until pH=10 is reached. Conc. HCl is added and theresulting solid is collected by filtration. Intermediate A-18a is usedwithout further purification for the next step.

The following intermediates A-18 (table 30) are available in ananalogous manner starting from different intermediates A-17.

TABLE 30 # structure t_(ret) [min] [M + H]⁺ HPLC method A-18a

1.22 331 A

Synthesis of Intermediate A-20 (Method O) Experimental Procedure for theSynthesis of A-20a and A-20b

Intermediate A-18a (100 mg, 0.30 mmol) is dissolved in NMP (3 mL) andNaH (38 mg, 1.51 mmol) is added at rt. The resulting mixture is stirredfor 5 min and A-19a is added. The reaction mixture is stirred at 70° C.for 15 h. Deionized water is added and the mixture is extracted withEtOAc. The layers are separated and the organic phase is washed withdeionized water and dried with MgSO₄. The solvents are removed underreduced pressure and the mixture is purified by reversed phase columnchromatography to yield A-20a and A-20b.

The following intermediates A-20 (table 31) are available in ananalogous manner starting from different intermediates A-18 and/or A-19.

TABLE 31 # structure t_(ret) [min] [M + H]⁺ HPLC method A-20a

1.38 474 A A-20b

1.38 474 A

Synthesis of Intermediate A-21 (Method P) Experimental Procedure for theSynthesis of A-21a

Intermediate A-20a (50 mg, 0.05 mmol) is dissolved in DCM (1 mL). TFA(40 μL) is added at 0° C. and the reaction mixture is slowly warmed tort. The reaction mixture is heated to reflux for 24 h and concentratedin vacuo. The residue is dissolved in EtOAc and water and aq. NaOH (4 M)is added until a pH of 12 is reached. The layers are separated and theaqueous phase is extracted with EtOAc. The combined organic layers aredried with MgSO₄. The solvents are removed under reduced pressure andthe mixture is purified by reversed phase column chromatography to yieldA-21a.

The following intermediates A-21 (Table 32) are available in ananalogous manner starting from different intermediates A-20.

TABLE 32 # structure t_(ret) [min] [M + H]⁺ HPLC method A-21a

1.14 374 A A-21b

1.14 374 A

Synthesis of Additional Intermediates A-15 (Method Q) ExperimentalProcedure for the Synthesis of A-15c (Alternative Synthesis, See AlsoMethod J)

Intermediate A-21a (20 mg, 0.027 mmol), 6-chloro-1H-indole-2,3-dioneS-1a (5 mg, 0.027 mmol) and triethylamine (17 μL, 0.13 mmol) aresuspended in anhydrous NMP (500 μL) in a microwave vial. The reactionvessel is sealed with a Teflon cap and irradiated for 45 min at a finaltemperature of 100° C. After cooling to rt the solvents are removedunder reduced pressure. The product is purified by reversed phase HPLCwhich gives intermediate A-15c.

The following intermediates A-15 (table 33) are available in ananalogous manner starting from different intermediates A-21 and/or S-1.

TABLE 33 # structure t_(ret) [min] [M + H]⁺ HPLC method A-15c

1.26 537 A A-15d

1.26 537 A A-15e

1.26 537 A A-15f

1.26 537 A

Synthesis of Further Compounds (Ib) According to the Invention (MethodK)

A-15a (0.030 g, 0.054 mmol) and 3-methyl-butyraldehyde (0.14 mg, 0.163mmol) are dissolved in acetic acid (1 mL) and sodiumtriacetoxyborohydride (0.06 g, 0.272 mmol) is added. The reactionmixture is allowed to stir at ambient temperature for 1 h before it isquenched by the careful addition of sat. aq. NaHCO₃ solution at 0° C.Deionized water and EtOAc are added and the phases are separated. Afterwashing with sat. aq. NaHCO₃ and water, the organic phase is dried withMgSO₄ and the solvent is removed under reduced pressure. Reversed phasecolumn chromatography gives pure Ib-64.

The following compounds (Ib) (table 34) are available in an analogousmanner starting from different intermediates A-15.

TABLE 34 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-64

0.90 621 G Ib-65

0.90 621 G Ib-66

1.55 619 A Ib-67

1.55 619 A Ib-68

0.78 579 G Ib-69

0.78 579 G Ib-70

0.83 593 G Ib-71

0.83 593 G Ib-72

0.87 607 G Ib-73

0.87 607 G Ib-74

0.90 621 G Ib-75

0.90 621 G Ib-76

0.88 619 G Ib-77

0.88 619 G Ib-78

n.a. n.a. n.a. Ib-79

n.a. n.a. n.a. Ib-80

0.81 637 G Ib-81

0.81 637 G Ib-82

0.88 651 G Ib-83

0.88 651 G Ib-84

0.67 671 G Ib-85

0.67 671 G Ib-86

0.93 633 G Ib-87

0.93 633 G Ib-88

0.95 647 G Ib-89

0.95 647 G Ib-90

0.81 647 G Ib-91

0.81 647 G Ib-92

0.88 685 D Ib-93

0.88 685 D Ib-94

0.87 685 G Ib-95

0.87 685 G Ib-96

1.11 671 K Ib-97

1.11 671 K Ib-98

1.13 671 K Ib-99

1.13 671 K

Synthesis of Further Compounds (Ib) According to the Invention (MethodL)

(3,3-difluorocyclobutyl)methanol (100 mg, 0.819 mmol) is dissolved inacetic acid (500 μL) and IBX (298 mg, 1.065 mmol) is added. The reactionmixture is stirred at 40° C. for 3 h before it is filtered through aplug of Celite©. To the filtrate, a solution of A-15a (30 mg, 0.054mmol) in acetic acid (500 μL) is added at rt. Sodiumtriacetoxyborohydride (58 mg, 0.272 mmol) is added in one portion to thereaction mixture and the reaction is allowed to stir at rt for 30 minbefore it is quenched by the careful addition of sat. aq. NaHCO₃solution at 0° C. Deionized water and EtOAc are added and the phases areseparated. After washing with sat. aq. NaHCO₃ and water, the organicphase is dried with MgSO₄ and the solvent is removed under reducedpressure. Reversed phase column chromatography gives pure Ib-100.

The following compounds (Ib) (table 35) are available in an analogousmanner starting from different intermediates A-15 and/or differentalcohols.

TABLE 35 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-100

0.82 655 G Ib-101

0.82 655 G Ib-102

0.78 656 G Ib-103

0.78 656 G Ib-104

0.96 621 D Ib-105

0.96 621 D

Synthesis of Further Compounds (Ib) by Ester Saponification ExperimentalProcedure for the Synthesis of Ib-106

Ib-3 (484 mg, 0.8 mmol) is dissolved in MeOH (10 mL) and aq. NaOHsolution (2 mL, 4 M) is added. The reaction mixture is heated to refluxfor 1 h. After acidification with 2 M aq. HCl and extraction with EtOActhe organic phase is dried with MgSO₄. Purification with reversed phaseHPLC leads to pure Ib-106.

The following compounds (Ib) (Table 36) are available in an analogousmanner starting from initially obtained compounds (Ib).

TABLE 36 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-106

1.21 591 A Ib-107

1.03 591 A Ib-108

1.03 591 A Ib-109

1.12 593 A Ib-110

1.08 593 A Ib-111

1.01 565 A Ib-112

1.01 565 A Ib-113

1.09 579 A Ib-114

1.09 579 A Ib-115

1.11 593 A Ib-116

1.11 593 A Ib-117

1.14 607 A Ib-118

1.14 607 A Ib-119

1.13 607 A Ib-120

1.13 607 A Ib-121

1.10 605 A Ib-122

1.10 605 A Ib-123

1.11 605 A Ib-124

1.11 605 A Ib-125

1.06 641 A Ib-126

1.06 641 A Ib-127

0.95 595 A Ib-128

0.95 595 A Ib-129

1.05 623 A Ib-130

1.05 623 A Ib-131

1.09 637 A Ib-132

1.09 637 A Ib-133

0.86 657 A Ib-134

0.86 657 A Ib-135

1.14 619 A Ib-136

1.14 619 A Ib-137

1.19 633 A Ib-138

1.19 633 A Ib-139

1.09 671 A Ib-140

1.09 671 A Ib-141

1.09 671 A Ib-142

1.08 671 A Ib-143

1.08 671 A Ib-144

1.12 671 A Ib-145

1.12 671 A Ib-146

1.09 633 A Ib-147

1.09 633 A Ib-148

1.03 642 A Ib-149

1.03 642 A Ib-150

1.15 607 A Ib-151

1.15 607 A Ib-152

0.97 582 A Ib-153

0.97 582 A Ib-154

1.03 591 A Ib-155

1.05 591 A Ib-156

0.97 591 A Ib-157

1.09 621 A Ib-158

1.16 675 A Ib-159

1.08 605 A Ib-160

1.05 605 A Ib-161

1.08 619 A Ib-162

1.14 633 A Ib-163

1.05 609 A Ib-164

1.12 659 A Ib-165

1.11 631 A Ib-166

1.11 631 A Ib-167

1.11 633 A Ib-168

1.11 633 A Ib-169

1.05 605 A Ib-170

1.05 605 A Ib-171

1.02 592 A Ib-172

1.02 592 A Ib-173

1.08 672 A Ib-174

1.08 672 A Ib-175

1.08 577 A Ib-176

1.01 577 A Ib-177

1.01 577 A Ib-178

0.99 577 A Ib-179

0.99 577 A Ib-180

0.99 577 A Ib-181

1.13 657 A Ib-182

1.13 657 A Ib-183

1.05 657 A Ib-184

1.05 657 A Ib-185

1.05 657 A Ib-186

1.08 657 A Ib-187

1.08 657 A Ib-188

1.05 591 A Ib-189

1.01 591 A Ib-190

1.02 591 A Ib-191

0.99 565 A Ib-192

0.99 565 A Ib-193

1.03 645 A Ib-194

1.03 645 A Ib-195

1.08 645 A Ib-196

1.08 645 A Ib-197

1.10 661 A Ib-198

1.06 621 A Ib-199

1.06 621 A Ib-200

1.01 565 A Ib-201

1.01 565 A Ib-202

1.03 565 A Ib-203

1.03 565 A Ib-204

1.01 605 A Ib-205

1.02 605 A Ib-206

1.01 605 A Ib-207

1.03 606 A Ib-208

1.03 606 A

Synthesis of Further Compounds (Ib) by Amidation Experimental Procedurefor the Synthesis of Ib-209

Ib-107 (52 mg, 0.09 mmol) is dissolved in anhydrous DMF (1 mL) and HATU(40 mg, 0.11 mmol) is added at rt. After addition of DIPEA (44.7 μL,0.26 mmol) the reaction mixture is allowed to stir at rt for 15 min.Methyl amine (2 M in THF, 52.6 μL, 0.11 mmol) is added and the reactionis allowed to stir for additional 30 min. The crude reaction mixture issubmitted to reversed phase column chromatography yielding pure Ib-209.

The following compounds (Ib) (table 37) are available in an analogousmanner starting from initially obtained compounds (Ib).

TABLE 37 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-209

1.34 604 A Ib-210

1.29 590 A Ib-211

1.39 618 A Ib-212

1.36 630 A Ib-213

1.32 662 A Ib-214

1.22 664 A Ib-215

1.25 634 A Ib-216

1.34 648 A Ib-217

1.38 692 A Ib-218

1.23 694 A Ib-219

1.37 692 A Ib-220

1.35 660 A Ib-221

1.34 673 A Ib-222

1.35 633 A Ib-223

1.37 661 A Ib-224

1.29 596 A Ib-225

1.34 660 A Ib-226

1.34 674 A Ib-227

1.26 646 A Ib-228

1.33 659 A Ib-229

1.27 676 A Ib-230

1.34 620 A Ib-231

1.28 606 A Ib-232

1.32 592 A Ib-233

1.36 606 A Ib-234

1.34 620 A Ib-235

1.38 634 A Ib-236

1.40 648 A Ib-237

1.34 618 A Ib-238

1.27 590 A Ib-239

1.25 576 A Ib-240

1.29 590 A Ib-241

1.36 656 A Ib-242

1.36 656 A Ib-243

1.36 656 A Ib-244

1.33 672 A

Synthesis of Further Compounds (Ib) by Ester Reduction ExperimentalProcedure for the Synthesis of Ib-245

Ib-3 (30 mg, 0.05 mmol) is dissolved in anhydrous toluene (1 mL) and asolution of Red-A1® (60% in toluene, 48 μL) is added. The reactionmixture is heated to 90° C. for 16 h. After that period of time,additional Red-A1 (24 μL) is added and heating is continued for 1 h. Thereaction is quenched by the addition of water and extracted with EtOAc.The organic layer is dried with MgSO₄ and solvents are removed underreduced pressure. Reversed phase column chromatography gives pureIb-245.

The following compounds (Ib) (table 38) are available in an analogousmanner starting from initially obtained compounds (Ib).

TABLE 38 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-245

1.38 577 A Ib-246

1.38 577 A

Synthesis of Further Compounds (Ib) by Deacylation ExperimentalProcedure for the Synthesis of Ib-247

Ib-59 (55 mg, 0.09 mmol) is dissolved in MeOH (500 μL) and conc. aq. HCl(37%, 40 μL) is added. The reaction mixture is heated to 65° C. for 3 h.The reaction is quenched by the addition of 4 M NaOH and EtOAc. Thephases are separated and the organic phase is dried with MgSO₄. Afterremoval of the solvents under reduced pressure, reversed phase columnchromatography gives Ib-247.

The following compounds (Ib) (table 39) are available in an analogousmanner starting from initially obtained compounds (Ib).

TABLE 39 # structure t_(ret) [min] [M + H]⁺ HPLC method I-247

1.35 562 A I-248

1.35 562 A

Synthesis of Further Compounds (Ib) by Reductive Amination ExperimentalProcedure for the Synthesis of Ib-249

Glutyraldehyde (25% in water, 20 μL, 0.055 mmol) is dissolved in DMF(600 μL) and Ib-247 (10 mg, 0.018 mmol) is added as a solution in DMF(400 μL). The reaction mixture is treated with AcOH (5.1 μL, 0.05 mmol)and stirred at rt for 15 min. After that period of time, sodiumtriacetoxyborohydride (11.3 mg, 0.05 mmol) is added in one portion andthe reaction mixture is allowed to stir at ambient temperature for 2 h.The reaction is quenched by the addition of water, filtered throughsyringe filter and purified by reversed phase column chromatography togive Ib-249.

The following compounds (Ib) (Table 40) are available in an analogousmanner starting from different compounds (Ib).

TABLE 40 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-249

1.64 630 A Ib-250

1.64 630 A Ib-251

1.35 562 A Ib-252

1.35 562 A

Synthesis of Further Compounds (Ib) by Amine Cleavage ExperimentalProcedure for the Synthesis of Ib-253

Ib-247 (12 mg, 0.021 mmol) is added to a mixture of hypophosphorous acid(50% in water, 300 μL, 2.7 mmol), sulfuric acid (15 μL, 0.26 mmol), andcopper(II)sulfate (3.75 mg, 0.023 mmol). The reaction mixture is stirredat rt for 5 min before sodium nitrite (6 mg, 0.085 mmol) and a couple ofdrops of water are added. The reaction is allowed to stir for 5 min.After quenching by the addition of diluted NaOH and extraction withEtOAc, phases are separated and the organic phase is dried with MgSO₄.Solvents are removed under reduced pressure and reversed phase columnchromatography yields pure Ib-253.

The following compounds (Ib) (table 41) are available in an analogousmanner starting from initially obtained compounds (Ib).

TABLE 41 # structure t_(ret) [min] [M + H]⁺ HPLC method Ib-253

1.51 547 A Ib-254

1.51 547 A

Compounds (Ic) General Reaction Scheme and Summary of the SynthesisRoute

Novel compounds of structure (Ic) can be prepared stepwise with asynthesis route depicted in scheme 6 starting from (hetero)aryl aminesC-1 via a copper-catalyzed three-component coupling reaction withprotected alkynylamines C-2 (e.g. bis- or mono-Boc protected) and anα,β-unsaturated aldehyde C-3 to build up imidazo ring systems (e.g.imidazopyrimidyl) C-4 (Angew. Chem. Int. Ed. 2010, 49, 2743). Theprotecting group(s) on C-4 can be removed by an appropriate method. Incase of mono- or di-Boc protection acidic conditions, like TFA indioxane, can be used to generate intermediate C-5. Intermediates C-6 canbe obtained from intermediates C-5 and isatin derivatives S-1 via a1,3-dipolar cycloaddition to build up spiro systems as a racemic mixturepotentially along with other regio- and/or diastereoisomers of C-6. Theenantiomers of C-6 can be separated at this stage by chiral SFC oralternatively the racemic mixture can be separated at any later stage ofthe synthesis. Also all other means known for separation of enantiomerscan be applied here or after any later synthetic step herein described,e.g. crystallisation, chiral resolution, chiral HPLC etc. (see alsoEnantiomers, racemates, and resolutions, Jean Jacques, André Collet,Samuel H Wilen John Wiley and Sons, N Y, 1981).

C-6 can be reacted with aldehydes or ketones in a reductive aminationreaction to yield compounds (Ic). Alternatively, an alkylation,addition, acylation or sulfonylation reaction can be performed with C-6to obtain additional compounds (Ic).

Compounds (Ic) which are initially obtained from C-6 can be derivatizedin optional derivatization steps not explicitly depicted in the schemesin all residues, especially in R⁴, if they carry functional groups, thatcan be further modified such as e.g. halogen atoms, amino and hydroxygroups (including cyclic amines), carboxylic acid or ester functions,nitrils etc. to further compounds (Ic) by well-established organicchemical transformations such as metal-catalyzed cross couplingreactions, acylation, amidation, addition, reduction or (reductive)alkylation or cleavage of protecting groups. These additional steps arenot depicted in the general schemes. Likewise, it is also possible toinclude these additional steps in the synthetic routes depicted in thegeneral schemes, i.e. to carry out derivatization reactions withintermediate compounds. In addition, it may also be possible thatbuilding blocks bearing protecting groups are used, i.e. further stepsfor deprotection are necessary.

Compounds (Ic) have been tested for their activity to affect MDM2-p53interaction in their racemic form or alternatively as the enantiopureform. Each of the two enantiomers of a racemic mixture may have activityagainst MDM2 although with a different binding mode. Enantiopurecompounds are marked with the label “Chiral”. Compounds listed in anytable below that are labeled “Chiral” (both intermediates as well ascompounds (Ic) according to the invention) can be separated by chiralSFC chromatography from their enantiomer or are synthesized fromenantiopure starting material which is separated by chiral SFC.

Structure A defines the racemic mixture of compounds with structure Band C, i.e. structure A encompasses two structures (compounds B and C),whereas structures B and C, respectively, are enantiopure and onlydefine one specific compound. Thus, formulae (Ic) and (Ic*)

with a set of specific definitions for groups R¹ to R⁷, A, V, W, X, Y,n, r and q represent the racemic mixture of two enantiomers (→(Ic);structure A above is one specific example of such a racemic mixture) ora single enantiomer (→(Ic*); structure B above is one specificenantiomer), unless there are additional stereocenters present in one ormore of the substituents. The same definition applies to syntheticintermediates.

Synthesis of Intermediates C-3 Experimental Procedure for the Synthesisof C-3a

2-Chloro-3-fluoro-pyridine-4-carbaldehyde D-1a (1.00 g, 6.27 mmol) and(triphenylphos-phoranylidene)acetaldehyde (1.91 g, 6.27 mmol) aredissolved in DMF and stirred at rt for 16 h. The mixture is poured intoice-water and the precipitate is filtered. The crude product is purifiedby chromatography to deliver intermediate C-3a.

The following intermediates C-3a (table 42) are available in ananalogous manner starting from different aldehydes D-1.

TABLE 42 # structure t_(ret) [min] [M + H]⁺ HPLC method C-3a

0.45 185 C

Synthesis of Intermediates C-4 Experimental Procedure for the Synthesisof C-4a (Method A)

2-Amino-isonicotinic acid methyl ester C-1a (1.00 g, 6.572 mmol), N-Bocprop-2-ynylamine C-2a (1.12 g, 7.230 mmol),E-3-(3-chloro-2-fluorophenyl) propenal C-3b (1.34 g, 7.23 mmol),Cu(OTf)₂ (0.24 g, 0.66 mmol) and CuCl (0.06 g, 0.07 mmol) are dissolvedin toluene under argon and stirred at 100° C. for 20 h. The solvent isremoved under vacuum and the crude product is purified by chromatographyto deliver intermediate C-4a.

The following intermediates C-4 (table 43) are available in an analogousmanner starting from different intermediates C-1, C-2 and C-3.

TABLE 43 # structure t_(ret) [min] [M + H]⁺ HPLC method C-4a

1.41 474 A C-4b

1.52 488 A C-4c

0.87 589 C C-4d

0.89 575 C C-4e

n.a. n.a. n.a

Synthesis of Intermediates C-5 Experimental Procedure for the Synthesisof C-5a (Method B)

Intermediate C-4a (1.00 g, 1.372 mmol) is dissolved in 1,4-dioxane andstirred at rt for 3 h. The solvent is removed under vacuum and the crudeproduct is purified by chromatography if necessary to deliverintermediate C-5a.

The following intermediates C-5 (table 44) are available in an analogousmanner starting from different intermediates C-4.

TABLE 44 # structure t_(ret) [min] [M + H]⁺ HPLC method C-5a

1.16 374 A C-5b

1.29 388 A C-5c

0.46 388 C C-5d

1.01 375 A C-5e

1.12 389 A C-5f

1.06 389 A

Synthesis of Intermediates C-6 Experimental Procedure for the Synthesisof C-6a (Method C)

A solution of intermediate C-5a (735 mg, 1.792 mmol), 6-chloroisatinS-1a (813 mg, 4.479 mmol) and N-methylpyrrolidine (763 mg. 8.958 mmol)in MeOH (30 mL) is heated under microwave irradiation at 120° C. for 20min. The reaction mixture is diluted with DCM and extracted with asaturated aqueous NaHCO₃ solution. The organic layer is separated andthe solvents are removed under vacuum and the resulting crude product ispurified by chromatography and reversed phase HPLC to deliverintermediate C-6a.

The following intermediates C-6 (table 45) are available in an analogousmanner starting from different intermediates C-5 and S-1.

TABLE 45 # structure t_(ret) [min] [M + H]⁺ HPLC method C-6a

0.677 537 C C-6b

0.677 537 C C-6c

n.a. n.a. — C-6d

n.a. n.a. — C-6e

n.a. n.a. — C-6f

n.a. n.a. — C-6g

1.17 538 A C-6h

1.17 538 A C-6i

1.23 552 A C-6j

1.23 552 A C-6k

1.23 552 A C-6l

1.23 552 A

Synthesis of Compounds (Ic) According to the Invention ExperimentalProcedure for the Synthesis of Ic-1 (Method D)

To a solution of cyclopropanecarbaldehyde (2.7 mg, 0.039 mmol) in AcOH(1 mL) is added intermediate C-6a (18 mg, 0.033 mmol) and the reactionmixture is stirred for 15 min. Sodium triacetoxyborohydride (14.2 g,0.065 mmol) is added and the reaction mixture is stirred overnight.Water is added to the reaction mixture and it is extracted with EtOAc.The combined organic layer is dried (MgSO₄), filtered, concentrated invacuo and the crude product is purified by chromatography to givecompound Ic-1.

The following compounds (Ic) (table 46) are available in an analogousmanner starting from different intermediates C-6 and differentaldehydes.

TABLE 46 # structure t_(ret) [min] [M + H]⁺ HPLC method Ic-1

1.50 1.50 A Ic-2

1.50 1.50 A Ic-3

n.a. n.a. — Ic-4

n.a. n.a. — Ic-5

n.a. n.a. — Ic-6

n.a. n.a. — Ic-7

1.44 592 A Ic-8

1.44 592 A Ic-9

1.44 592 A Ic-10

1.44 592 A Ic-11

n.a. n.a. — Ic-12

n.a. n.a. — Ic-13

1.57 686 A Ic-14

1.57 686 A

Synthesis of Further Compounds (Ic) by Ester Saponification ExperimentalProcedure for the Synthesis of Ic-15 (Method E)

Ic-1 (12 mg, 0.022 mmol) is dissolved in THE (0.5 mL) and water (1 mL)and NaOH s (25 mg, 0.45 mmol) is added. The reaction mixture is stirredat 70° C. for 8 h. After acidification with 2 M aq. HCl and extractionwith EtOAc the organic phase is dried with MgSO₄. Purification withreversed phase HPLC leads to pure Ic-15.

The following compounds (Ic) (table 47) are available in an analogousmanner starting from initially obtained compounds (Ic).

TABLE 47 # structure t_(ret) [min] [M + H]⁺ HPLC method Ic-15

577 1.05 A Ic-16

577 1.05 A Ic-17

n.a. n.a. — Ic-18

n.a. n.a. — Ic-19

n.a. n.a. — Ic-20

n.a. n.a. — Ic-21

n.a. n.a. — Ic-22

n.a. n.a. — Ic-23

0.99 592 A Ic-24

0.99 592 A Ic-25

n.a. n.a. — Ic-26

n.a. n.a. — Ic-27

1.06 672 A Ic-28

1.06 672 A

Synthesis of Further Compounds (Ic) by Amidation Experimental Procedurefor the Synthesis of Ic-29 (Method F)

Ic-23 (7 mg, 0.012 mmol) is dissolved in anhydrous THE (1 mL) and HATU(5 mg, 0.05 mmol) is added at rt. After addition of DIPEA (5 mg, 0.05mmol) the reaction mixture is allowed to stir at rt for 15 min.Dimethylamine (4 mg, 0.035 mmol) is added and the reaction is allowed tostir for additional 60 min. The crude reaction mixture is submitted toreversed phase column chromatography yielding pure Ic-29.

The following compounds (Ic) (table 48) are available in an analogousmanner starting from initially obtained compounds (Ic).

TABLE 48 # structure t_(ret) [min] [M + H]⁺ HPLC method Ic-29

1.30 619 A Ic-30

1.30 619 A Ic-31

0.63 646 C Ic-32

0.63 646 C Ic-33

0.70 644 C Ic-34

0.70 644 C Ic-35

1.45 659 A Ic-36

1.45 659 A Ic-37

1.29 661 A Ic-38

1.29 661 A

The following Examples describe the biological activity of the compoundsaccording to the invention, without restricting the invention to theseExamples.

Compounds of formulae (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and (Ic*) arecharacterised by their many possible applications in the therapeuticfield. Particular mention should be made of those applications in whichthe inhibiting effect on the proliferation of cultivated human tumourcells but also on the proliferation of other cells such as endothelialcells, for example, are involved.

Mdm2-p53 Inhibition AlphaScreen

This assay is used to determine whether the compounds inhibit thep53-MDM2 interaction and thus restore p53 function.

15 μL of compound in 20% DMSO (serial pre-dilutions of compound are donein 100% DMSO) is pipetted to the wells of a white OptiPlate-96(PerkinElmer). A mix consisting of 20 nM GST-MDM2 protein (aa 23-117)and 20 nM biotinylated p53 wt peptide (encompassing aa 16-27 of wt humanp53, amino acid sequence QETFSDLWKLLP-Ttds-Lys-Biotin, molecular weight2132.56 g/mol) is prepared in assay buffer (50 mM Tris/HCl pH 7.2; 120mM NaCl; 0.1% bovine serum albumin (BSA); 5 mM dithiothreitol (DTT); 1mM ethylenediaminetetraacetic acid (EDTA); 0.01% Tween 20). 30 μL of themix is added to the compound dilutions and incubated for 15 min at rtwhile gently shaking the plate at 300 rounds per minute (rpm).Subsequently, 15 μL of premixed AlphaLISA Glutathione Acceptor Beads andAlphaScreen Streptavidin Donor Beads from PerkinElmer (in assay bufferat a concentration of 10 μg/mL each) are added and the samples areincubated for 30 min at rt in the dark (shaking 300 rpm). Afterwards,the signal is measured in a PerkinElmer Envision HTS Multilabel Readerusing the AlphaScreen protocol from PerkinElmer.

Each plate contains negative controls where biotinylated p53-peptide andGST-MDM2 are left out and replaced by assay buffer. Negative controlvalues are entered as low basis value when using the software GraphPadPrism for calculations. Furthermore, a positive control (5% DMSO insteadof test compound; with protein/peptide mix) is pipetted. Determinationof IC₅₀ values are carried out using GraphPad Prism 3.03 software (orupdates thereof). Table 49 shows the IC₅₀ values of example compoundsdetermined using the above assay.

TABLE 49 IC₅₀ MDM2 # [nM] Ia-20 23 Ia-25 2 Ia-26 4 Ia-27 2 Ia-29 2 Ia-302 Ia-31 3 Ia-32 2 Ia-33 3 Ia-34 2 Ia-35 2 Ia-36 5 Ia-38 2 Ia-39 4 Ia-402 Ia-41 3 Ia-43 2 Ia-46 8 Ia-47 9 Ia-48 10 Ia-49 6 Ia-50 4 Ia-51 7 Ia-5269 Ia-53 7 Ia-54 13 Ia-55 6 Ia-56 5 Ia-57 13 Ib-49 5 Ib-57 12 Ib-58 7Ib-59 15 Ib-66 166 Ib-106 3 Ib-107 2 Ib-108 79 Ib-109 8 Ib-110 3 Ib-1117 Ib-113 4 Ib-115 7 Ib-117 8 Ib-119 12 Ib-121 11 Ib-123 4 Ib-125 14Ib-127 11 Ib-129 10 Ib-131 22 Ib-133 58 Ib-135 15 Ib-137 34 Ib-139 4Ib-140 2 Ib-141 48 Ib-142 3 Ib-144 8 Ib-146 11 Ib-148 21 Ib-150 20Ib-152 7 Ib-154 3 Ib-155 2 Ib-156 5 Ib-157 2 Ib-158 3 Ib-159 7 Ib-160 4Ib-161 11 Ib-162 6 Ib-163 2 Ib-164 3 Ib-165 28 Ib-167 22 Ib-169 7 Ib-17110 Ib-173 7 Ib-175 3 Ib-176 2 Ib-177 53 Ib-178 4 Ib-179 2 Ib-180 83Ib-183 3 Ib-184 2 Ib-185 14 Ib-186 4 Ib-188 3 Ib-189 3 Ib-190 2 Ib-191 6Ib-193 3 Ib-195 6 Ib-197 2 Ib-198 4 Ib-200 3 Ib-202 7 Ib-204 2 Ib-205 3Ib-206 4 Ib-207 8 Ib-209 3 Ib-210 4 Ib-211 11 Ib-212 5 Ib-213 7 Ib-214 3Ib-215 4 Ib-216 7 Ib-217 4 Ib-218 6 Ib-219 5 Ib-220 10 Ib-221 10 Ib-2229 Ib-223 5 Ib-224 4 Ib-225 5 Ib-226 5 Ib-227 4 Ib-228 5 Ib-229 4 Ib-23010 Ib-231 4 Ib-232 3 Ib-233 4 Ib-234 2 Ib-235 3 Ib-236 5 Ib-237 10Ib-238 6 Ib-239 3 Ib-240 3 Ib-241 4 Ib-242 2 Ib-243 99 Ib-244 3 Ib-24520 Ib-247 27 Ib-249 240 Ib-251 68 Ib-253 72 Ic-23 6 Ic-27 13 Ic-29 10Ic-35 10 Ic-37 10

Cell Proliferation Assays

Cell Titer Glo assay for e.g. SJSA-1, SKOV-3, RS4-11 and KG-1 cells:

SJSA-1 cells (Osteosarcoma, wild-type p53, ATCC CRL-2098™) are seeded induplicates at day 1 in flat bottom 96 well microtiter plates (whitePackard View Plate 96 well Cat. No. 6005181) in 90 μL RPMI medium, 10%fetal calf serum (FCS, from e.g. JRH Biosciences #12103-500M, Lot.:3N207) at a density of 2500 cells/well. Any other luminescencecompatible plate format is possible.

Similarly, p53 mutant SKOV-3 cells (ovarian adenocarcinoma, ATCCHTB-77™) are seeded in duplicates in flat bottom 96 well microtiterplates in 90 μL McCoy medium, 10% FCS at a density of 3000 cells/well.

At day 2, 5 μL dilutions of the test compounds covering a concentrationrange between app. 0.6 and 50000 nM are added to the cells. Cells areincubated for three days in a humidified, CO₂-controlled incubator at37° C.

wildtype p53 RS4-11 cells (acute lymphoblastic leukemia, ATCCCRL-1873™):

Day 1: RS4-11 cells are seeded in flat bottom 96 well microtiter plates(white Packard View Plate 96 well Cat. No. 6005181) in 90 μL RPMImedium, 10% fetal calf serum (FCS, from e.g. JRH Biosciences#12103-500M, Lot.: 3N0207) at a density of 5000 cells/well. Any otherluminescence compatible plate format is possible.

Day 2: 5 μL dilutions of the test compounds covering a concentrationrange between app. 0.3 and 25000 nM (alternative dilution schemes arepossible) are added to the cells. Cells are incubated for three days ina humidified, CO₂ controlled incubator at 37° C. The finalDMSO-concentration is 0.5%.

p53 mutant KG-1 cells (acute myelogenous leukemia, ATCC CCL-246):

Day 1: KG-1 cells harboring a p53 mutation at the exon 6/intron 6 splicedonor site are seeded in flat bottom 96 well microtiter plates (whitePackard View Plate 96 well Cat. No. 6005181) in 90 μL IMDM medium, 10%FCS (JRH Biosciences #12103-500M, Lot.: 3N0207) at a density of 10000cells/well. Any other luminescence compatible plate format is possible.

Day 2: 5 μL dilutions of the test compounds covering a concentrationrange between app. 0.3 and 25000 nM (alternative dilution schemes arepossible) are added to the cells. Cells are incubated for three days ina humidified, CO₂ controlled incubator at 37° C. The finalDMSO-concentration is 0.5%.

Evaluation of all Cell Titer Glo assays is done at day 5 after seeding.At day 5, 95 μL of Cell Titer Glo reagent (Cell titer Glo LuminescentCat. No. G7571, Promega) are added to each well and incubated foradditional 10 min at rt (with agitation). Luminescence is measured on aWallac Victor using standard luminescence read out. IC₅₀ values arecalculated using standard Levenburg Marquard algorithms (GraphPadPrism).

In addition, several other cancer cell lines from diverse tissue originsare sensitive to compounds (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) and(Ic*). Examples include NCI-H460 (lung), Molp-8 (myeloma) and MV4-11(AML).

On the basis of their biological properties the compounds of formula(I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or (Ic*) according to the invention,their tautomers, racemates, enantiomers, diastereomers, mixtures thereofand the salts of all the above-mentioned forms are suitable for treatingdiseases characterised by excessive or abnormal cell proliferation.

Such diseases include for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g.psoriasis); diseases based on hyperplasia which are characterised by anincrease in the number of cells (e.g. fibroblasts, hepatocytes, bonesand bone marrow cells, cartilage or smooth muscle cells or epithelialcells (e.g. endometrial hyperplasia); bone diseases and cardiovasculardiseases (e.g. restenosis and hypertrophy). They are also suitable forprotecting proliferating cells (e.g. hair, intestinal, blood andprogenitor cells) from DNA damage caused by radiation, UV treatmentand/or cytostatic treatment.

For example, the following cancers/proliferative diseases may be treatedwith compounds according to the invention, without being restrictedthereto:

brain tumours such as for example acoustic neurinoma, astrocytomas suchas pilocytic astrocytomas, fibrillary astrocytoma, protoplasmicastrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma andglioblastoma, glioma, brain lymphomas, brain metastases, hypophysealtumour such as prolactinoma, HGH (human growth hormone) producing tumourand ACTH producing tumour (adrenocorticotropic hormone),craniopharyngiomas, medulloblastomas, meningeomas andoligodendrogliomas; nerve tumours (neoplasms) such as for exampletumours of the vegetative nervous system such as neuroblastomasympathicum, ganglioneuroma, paraganglioma (pheochromocytoma,chromaffinoma) and glomus-caroticum tumour, tumours on the peripheralnervous system such as amputation neuroma, neurofibroma, neurinoma(neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumoursof the central nervous system such as brain and bone marrow tumours;intestinal cancer such as for example carcinoma of the rectum, coloncarcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the largebowel, tumours of the small intestine and duodenum; eyelid tumours suchas basalioma or basal cell carcinoma; pancreatic cancer or carcinoma ofthe pancreas; bladder cancer or carcinoma of the bladder and otherurothelial cancers; lung cancer (bronchial carcinoma) such as forexample small-cell bronchial carcinomas (oat cell carcinomas) andnon-small cell bronchial carcinomas (NSCLC) such as plate epithelialcarcinomas, adenocarcinomas and large-cell bronchial carcinomas; breastcancer such as for example mammary carcinoma such as infiltrating ductalcarcinoma, colloid carcinoma, lobular invasive carcinoma, tubularcarcinoma, adenocystic carcinoma and papillary carcinoma, hormonereceptor positive breast cancer (estrogen receptor positive breastcancer, progesterone receptor positive breast cancer), Her2 positivebreast cancer, triple negative breast cancer; non-Hodgkin's lymphomas(NHL) such as for example Burkitt's lymphoma, low-malignancynon-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer orendometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer ofUnknown Primary); ovarian cancer or ovarian carcinoma such as mucinous,endometrial or serous cancer; gall bladder cancer; bile duct cancer suchas for example Klatskin tumour; testicular cancer such as for exampleseminomas and non-seminomas; lymphoma (lymphosarcoma) such as forexample malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, leukaemicreticuloendotheliosis, immunocytoma, plasmocytoma, multiple myeloma(MM), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides,large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngealcancer such as for example tumours of the vocal cords, supraglottal,glottal and subglottal laryngeal tumours; bone cancer such as forexample osteochondroma, chondroma, chondroblastoma, chondromyxoidfibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilicgranuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing'ssarcoma, reticulo-sarcoma, soft tissue sarcoma, liposarcoma,plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmaticbone cysts; head and neck tumours such as for example tumours of thelips, tongue, floor of the mouth, oral cavity, gums, palate, salivaryglands, throat, nasal cavity, paranasal sinuses, larynx and middle ear;liver cancer such as for example liver cell carcinoma or hepatocellularcarcinoma (HCC); leukaemias, such as for example acute leukaemias suchas acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloidleukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia(CLL), chronic myeloid leukaemia (CML); myelodysplastic syndromes (MDS);stomach cancer or gastric carcinoma such as for example papillary,tubular and mucinous adenocarcinoma, signet ring cell carcinoma,adenosquamous carcinoma, small-cell carcinoma and undifferentiatedcarcinoma; melanomas such as for example superficially spreading,nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancersuch as for example kidney cell carcinoma or hypernephroma or Grawitz'stumour; oesophageal cancer or carcinoma of the oesophagus; penilecancer; prostate cancer (e.g. castration-resistant prostate cancer);throat cancer or carcinomas of the pharynx such as for examplenasopharynx carcinomas, oropharynx carcinomas and hypopharynxcarcinomas; retinoblastoma, vaginal cancer or vaginal carcinoma,mesothelioma; plate epithelial carcinomas, adenocarcinomas, in situcarcinomas, malignant melanomas and sarcomas; thyroid carcinomas such asfor example papillary, follicular and medullary thyroid carcinoma, aswell as anaplastic carcinomas; spinalioma, epidormoid carcinoma andplate epithelial carcinoma of the skin; thymomas, cancer of the urethra,cervical cancer, adenoid cystic carcinoma (AdCC), adrenocorticalcarcinoma and cancer of the vulva.

Preferably, the proliferative diseases/cancers to be treated havefunctional p53 and/or p53 wild-type status. Functional p53 means thatp53 is able to bind to DNA and activate transcription of target genes.

The new compounds may be used for the prevention, short-term orlong-term treatment of the above-mentioned diseases, optionally also incombination with radiotherapy or other “state-of-the-art” compounds,such as e.g. cytostatic or cytotoxic substances, cell proliferationinhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of formula formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or(Ic*) may be used on their own or in combination with other activesubstances according to the invention, optionally also in combinationwith other pharmacologically active substances.

Therapeutic agents (=cytostatic and/or cytotoxic active substances)which may be administered in combination with the compounds according tothe invention, include, without being restricted thereto, hormones,hormone analogues and antihormones (e.g. tamoxifen, toremifene,raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide,bicalutamide, aminoglutethimide, cyproterone acetate, finasteride,buserelin acetate, fludrocortisone, fluoxymesterone,medroxyprogesterone, octreotide), aromatase inhibitors (e.g.anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane),LHRH agonists and antagonists (e.g. goserelin acetate, luprolide),inhibitors of growth factors (growth factors such as for example“platelet derived growth factor (PDGF)”, “fibroblast growth factor(FGF)”, “vascular endothelial growth factor (VEGF)”, “epidermal growthfactor (EGF)”, “insuline-like growth factors (IGF)”, “human epidermalgrowth factor (HER, e.g. HER2, HER3, HER4)” and “hepatocyte growthfactor (HGF)”), inhibitors are for example “growth factor” antibodies,“growth factor receptor” antibodies and tyrosine kinase inhibitors, suchas for example cetuximab, gefitinib, imatinib, lapatinib, bosutinib andtrastuzumab); antimetabolites (e.g. antifolates such as methotrexate,raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU),capecitabine and gemcitabine, purine and adenosine analogues such asmercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (araC), fludarabine); antitumour antibiotics (e.g. anthracyclins such asdoxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride,myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicinand idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin,streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin,carboplatin); alkylation agents (e.g. estramustin, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide,ifosfamide, temozolomide, nitrosoureas such as for example carmustin andlomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such asfor example vinblastine, vindesin, vinorelbin and vincristine; andtaxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g.tasquinimod), tubuline inhibitors; DNA synthesis inhibitors (e.g.sapacitabine), PARP inhibitors, topoisomerase inhibitors (e.g.epipodophyllotoxins such as for example etoposide and etopophos,teniposide, amsacrin, topotecan, irinotecan, mitoxantrone),serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors, Rafinhibitors, A-Raf inhibitros, B-Raf inhibitors, C-Raf inhibitors, mTORinhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dualmTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosinekinase inhibitors (e.g. PTK2/FAK inhibitors), protein proteininteraction inhibitors (e.g. IAP activator, Mcl-1, MDM2/MDMX), MEKinhibitors (e.g. pimasertib), ERK inhibitors, FLT3 inhibitors (e.g.quizartinib), BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists,Bcl-xL inhibitors, Bcl-2 inhibitors (e.g. venetoclax), Bcl-2/Bcl-xLinhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABLinhibitors, Src inhibitors, rapamycin analogs (e.g. everolimus,temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors(e.g. abiraterone, TAK-700), androgen receptor inhibitors (e.g.enzalutamide, ARN-509), immunotherapy (e.g. sipuleucel-T), DNMTinhibitors (e.g. SGI 110, temozolomide, vosaroxin), HDAC inhibitors(e.g. vorinostat, entinostat, pracinostat, panobinostat), ANG1/2inhibitors (e.g. trebananib), CYP17 inhibitors (e.g. galeterone),radiopharmaceuticals (e.g. radium-223, alpharadin), immunotherapeuticagents (e.g. poxvirus-based vaccine, ipilimumab, immune checkpointinhibitors) and various chemotherapeutic agents such as amifostin,anagrelid, clodronat, filgrastin, interferon, interferon alpha,leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane,pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine,2-fluorodesoxycytidine, 2-methoxyoestradiol, 2C4, 3-alethine,131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,ABT-199, ABT-263/navitoclax, ABT-737, A 105972, A 204197, aldesleukin,alisertib/MLN8237, alitretinoin, allovectin-7, altretamine, alvocidib,amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine,aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE,AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), AMG-232, AMG-511, AMG2520765, AMG 2112819, ARRY 162, ARRY 438162, ARRY-300,ARRY-142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330, ATSP-7041, AR-12,AR-42, AS-703988, AXL-1717, AZD-1480, AZD-4547, AZD-8055, AZD-5363,AZD-6244, AZD-7762, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin,AZD-2014, azacitidine (5-aza), azaepothilone B, azonafide,barasertib/AZD1152, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576,bevacizumab, BEZ-235/dactolisib, biricodar dicitrate, birinapant,BCX-1777, BKM-120/buparlisib, bleocin, BLP-25, BMS-184476, BMS-247550,BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992/afatinib, BIBF 1120/nintedanib, BI 836845, BI 2536, BI6727/volasertib, BI 836845, BI 847325, BI 853520, BIIB-022, bleomycinicacid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib,brostallicin, busulphan, BYL-719/alpelisib, CA-4 prodrug, CA-4,cabazitaxel, cabozantinib, CapCell, calcitriol, canertinib,canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CC-115,CC-223, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone,celecoxib, celmoleukin, cemadotin, CGM-097, CH4987655/RO-4987655,chlorotrianisene, cilengitide, ciclosporin, CD20 antibodies, CDA-II,CDC-394, CKD-602, CKI-27, clofarabine, colchicin, combretastatin A4, COTinhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin 52,CPI-613, CTP-37, CTLA-4 monoclonal antibodies (e.g. ipilimumab), CP-461,crizotinib, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851,dasatinib, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin,depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet,diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10,doranidazole, DS-7423, DS-3032, E7010, E-6201, edatrexat, edotreotide,efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509,enzastaurin, elesclomol, elsamitrucin, epothilone B, epratuzumab,EPZ-004777, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine,ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind,fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4,FOLFIRI, formestane, fostamatinib, fotemustine, galarubicin, galliummaltolate, ganetespib, gefinitib, gemtuzumab, gemtuzumab ozogamicin,gimatecan, glufosfamide, GCS-IOO, GDC-0623, GDC-0941 (pictrelisib),GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK,GMX-1778, GPX-100, gp100-peptide vaccines, GSK-5126766, GSK-690693,GSK-1120212 (trametinib), GSK-1995010, GSK-2118436 (dabrafenib),GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795,GSK-2636771, GSK-525762A/I-BET-762, GW2016, granisetron, herceptine,hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid,hydroxyurea, hydroxyprogesterone caproate, HDM-201, ibandronate,ibritumomab, ibrutinib/PCI-32765, idasanutlin, idatrexate,idelalisib/CAL-101, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11,IMC-A12 (cixutumumab), immunol, indisulam, interferon alpha-2a,interferon alpha-2b, pegylated interferon alpha-2b, interleukin-2,INK-1117, INK-128, INSM-18, ionafarnib, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, JQ-1, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, KU-55933, LCL-161, lobaplatin, leflunomide,lenalidomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550,linezolid, lovastatin, lutetium texaphyrin, lometrexol, lonidamine,losoxantrone, LU 223651, lurbinectedin, lurtotecan, LY-S6AKT1,LY-2780301, LY-2109761/galunisertib, mafosfamide, marimastat,masoprocol, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, MLN-0128, MLN-2480,motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neratinib,Nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed,norelin, N-acetylcysteine, NU-7441 06-benzylguanine, oblimersen,omeprazole, olaparib, oncophage, oncoVEX^(GM-CSF), ormiplatin,ortataxel, OX44 antibodies, OSI-027, OSI-906 (linsitinib), 4-1BBantibodies, oxantrazole, oestrogen, onapristone, palbociclib/PD-0332991,panitumumab, panobinostat, patupilone, pazopanib, pegfilgrastim,PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PD0325901, PD-1 and PD-L1antibodies (e.g. pembrolizumab, nivolumab, pidilizumab,MEDI-4736/durvalumab, RG-7446/atezolizumab), PD-616, PEG-paclitaxel,albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384,PF-04691502, PF-3758309, PHA-665752, PHT-427, P-04, PKC412, P54, PI-88,pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, pertuzumab,pevonedistat, P13K inhibitors, P13K/mTOR inhibitors, PG-TXL, PG2,PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054, PT-100,PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone,phenoxodiol O, PK1166, plevitrexed, plicamycin, polyprenic acid,ponatinib, porfiromycin, posaconazole, prednisone, prednisolone,PRT-062607, quinamed, quinupristin, quizartinib/AC220, R115777, RAF-265,ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436, rebeccamycinanalogues, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167,RG-7112, RG-7304, RG-7421, RG-7321, RG-7356, RG 7440, RG-7775, rhizoxin,rhu-MAb, rigosertib rinfabate, risedronate, rituximab, robatumumab,rofecoxib, romidepsin, RO-4929097, RO-31-7453, RO-5126766, RO-5068760,RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201,ruxolitinib, S-9788, sabarubicin, SAHA, sapacitabine, SAR-405838,sargramostim, satraplatin, SB-408075, SB-431542, Se-015/Ve-015, SU5416,SU6668, SDX-101, selinexor, semustin, seocalcitol, SM-11355, SN-38,SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin,squalamine, STF-31, suberanilohydroxamic acid, sutent, T 900607, T138067, TAE-684, TAK-733, TAS-103, tacedinaline, talaporfin,tanespimycin, Tarceva, tariquitar, tasisulam, taxotere, taxoprexin,tazarotene, tegafur, temozolamide, tesmilifene, testosterone,testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin,tezacitabine, thalidomide, theralux, therarubicin, thymalfasin,thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex,toremofin, tosedostat. trabectedin, TransMID-107, transretinic acid,traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine,triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin,valproic acid, valrubicin, vandetanib, vatalanib, vincristine,vinflunine, virulizin, vismodegib, vosaroxin, WX-UK1, WX-554, vectibix,XAV-939, xeloda, XELOX, XL-147, XL-228, XL-281, XL-518/R-7420/GDC-0973,XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126,ZD-9331, ZD1839, ZSTK-474, zoledronat and zosuquidar.

Particularly preferred are methods of treatment and medical usesincluding the use of the compounds (I) of the invention in combinationwith immunotherapeutic agents, e.g. checkpoint inhibitors includinganti-PD-1 and anti-PD-L1 agents (such as e.g. pembrolizumab, nivolumab,pidilizumab, MEDI-4736/durvalumab and RG-7446/atezolizumab) andanti-LAG3 agents. Thus, one aspect of the invention are methods oftreatment and medical uses including the use of a compound (I) of theinvention in combination with an anti-PD-1 or an anti-PD-1 agent (suchas e.g. pembrolizumab, nivolumab, pidilizumab, MEDI-4736/durvalumab andRG-7446/atezolizumab). Another aspect of the invention are methods oftreatment and medical uses including the use of a compound (I) of theinvention in combination with an anti-LAG3 agent. A further aspect ofthe invention are methods of treatment and medical uses including theuse of a compound (I) of the invention in combination with an anti-PD-1agent and an anti-LAG3 agent.

Suitable preparations include for example tablets, pills, capsules,suppositories, lozenges, troches, solutions—particularly solutions forinjection (s.c., iv., i.m.) and infusion (injectables)—elixirs, syrups,sachets, emulsions, inhalatives or dispersible powders. The content ofthe pharmaceutically active compound(s) should be in the range from 0.1to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole,i.e. in amounts which are sufficient to achieve the dosage rangespecified below. The doses specified may, if necessary, be given severaltimes a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc, agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate, carriers, adjuvants, surfactants. The tablets mayalso comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may of course contain, apart from theabove-mentioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage range of the compounds of formula (I), (a), (Ib), (Ic),(Ia*), (Ib*) or (c*) applicable per day is usually from 1 mg to 2000 mg,preferably from 50 to 1000 mg, more preferably from 100 to 500 mg.

The dosage for intravenous use is from 1 mg to 1000 mg per hour,preferably between 5 mg and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present inventionwithout restricting its scope (active substance in all examples is acompound according to formula (I), (Ia), (Ib), (Ic), (Ia*), (Ib*) or(Ic*)):

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodiumcarboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Tablets per tablet active substance 25 mg lactose 50 mgmicrocrystalline cellulose 24 mg magnesium stearate 1 mg 100 mg

The active substance, lactose and cellulose are mixed together. Themixture is screened, then either moistened with water, kneaded,wet-granulated and dried or dry-granulated or directely final blend withthe magnesium stearate and compressed to tablets of suitable shape andsize. When wet-granulated, additional lactose or cellulose and magnesiumstearate is added and the mixture is compressed to produce tablets ofsuitable shape and size.

D) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

The invention claimed is:
 1. Intermediate of formula B-20

R² and R³, each independently, is selected from among hydrogen,C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl,wherein said C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl is optionally substituted by one or more, identical ordifferent R^(b2) and/or R^(c2); each R^(b2) is independently selectedfrom among —OR^(c2), —NR^(c2)R^(c2), halogen, —CN, —C(O)R^(c2),—C(O)OR^(c2), —C(O)NR^(c2)R^(c2), —S(O)₂R^(c2), —S(O)₂NR^(c2)R^(c2),—NHC(O)R^(c2), —N(C₁₋₄alkyl)C(O)R^(c2) and the bivalent substituent ═O,while ═O may only be a substituent in non-aromatic ring systems; eachR^(c2) independently of one another denotes hydrogen or a group,optionally substituted by one or more, identical or different R^(d2)and/or R^(e2), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl, 5-10membered heteroaryl and 3-10 membered heterocyclyl; each R^(d2) isindependently selected from among —OR^(e2), —NR^(e2)R^(e2), halogen,—CN, —C(O)R^(e2), —C(O)OR^(e2), —C(O)NR^(e2)R^(e2), —S(O)₂R^(e2),—S(O)₂NR^(e2)R^(e2), —NHC(O)R^(e2), —N(C₁₋₄alkyl)C(O)R^(e2) and thebivalent substituent ═O, while ═O may only be a substituent innon-aromatic ring systems; each R^(e2) independently of one anotherdenotes hydrogen or a group selected from among C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyl, C₆₋₁₀aryl,5-10 membered heteroaryl and 3-10 membered heterocyclyl; A is selectedfrom among phenyl and 5-6 membered heteroaryl; each R⁴ is independentlyselected from among R^(a4) and R^(b4); each R^(a4) independently of oneanother is a group, optionally substituted by one or more, identical ordifferent R^(b4) and/or R^(c4), selected from among C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl; each R^(b4) is independently selected from among —OR^(c4),—NR^(c4)R^(c4), halogen, —CN, —C(O)R^(c4), —C(O)OR^(c4),—C(O)NR^(c4)R^(c4), —C(O)NR^(g4)OR^(c4), —S(O)₂R^(c4),—S(O)₂NR^(c4)R^(c4), —NHSO₂R^(c4), —N(C₁₋₄alkyl)SO₂R^(c4), —NHC(O)R^(c4)and —N(C₁₋₄alkyl)C(O)R^(c4); each R^(c4) independently of one anotherdenotes hydrogen or a group, optionally substituted by one or more,identical or different R^(d4) and/or R^(e4), selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl,C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 3-10 memberedheterocyclyl; each R^(d4) is independently selected from among —OR^(e4),—NR^(e4)R^(e4), halogen, —CN, —C(O)R^(e4), —C(O)OR^(e4),—C(O)NR^(e4)R^(e4), —C(O)NR^(g4)OR^(e4), —S(O)₂R^(e4),—S(O)₂NR^(e4)R^(e4), —NHC(O)R^(e4) and —N(C₁₋₄alkyl)C(O)R^(e4); eachR^(e4) independently of one another denotes hydrogen or a group,optionally substituted by one or more, identical or different R^(f4)and/or R^(g4), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10membered heteroaryl and 3-10 membered heterocyclyl; each R^(f4) isindependently selected from among —OR^(g4), —NR^(g4)R^(g4), halogen,—CN, —C(O)R^(g4), —C(O)OR^(g4), —C(O)NR^(g4)R^(g4), —C(O)NR^(g4)OR^(g4),—S(O)₂R^(g4), —S(O)₂NR^(g4)R^(g4), —NHC(O)R^(g4) and—N(C₁₋₄alkyl)C(O)R^(g4); each R^(g4) is independently selected fromamong hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₃₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₆₋₁₀aryl, 5-10 membered heteroaryland 3-10 membered heterocyclyl; r denotes the number 0, 1, 2 or 3; eachR⁷ is independently selected from among halogen, C₁₋₄alkyl, —CN,C₁₋₄haloalkyl, —OC₁₋₄alkyl and —OC₁₋₄haloalkyl; q denotes the number 0,1, 2 or 3; V is oxygen or sulfur; and wherein W, X and Y is eachindependently selected from —N═ and —CH═, wherein the hydrogen in each—CH═ may be replaced by a substituent R⁷ if present and wherein amaximum of two of W, X and Y can be —N═, or a salt thereof.
 2. A methodfor synthesizing an intermediate of formula B-20

comprising reacting a compound B-2

with an imine B-19

wherein R², R³, R⁴, R⁷, A, V, r and q are as defined in claim 1, andwherein W, X and Y is each independently selected from —N═ and —CH═,wherein the hydrogen in each —CH═ may be replaced by a substituent R⁷ ifpresent and wherein a maximum of two of W, X and Y can be —N═.